Karen J. Brasel MD, MPH, FACS

• Associate Professor, Departments of Surgery and Health Policy, Medical College of
• Wisconsin, Milwaukee, Wisconsin

Signal Processing Begins in the Retina We now move from the cellular mechanism of light transduction to the processing of light signals by the retina and brain symptoms 8 days past ovulation purchase persantine canada, the third and final step in our vision pathway medicine used to treat chlamydia cheap persantine 100 mg otc. When activated by as little as one photon of light medicine of the prophet buy discount persantine 100mg line, retinal changes shape to a new configuration treatment croup cheap 100 mg persantine otc. The activated retinal no longer binds to opsin and is released from the pigment in the process known as bleaching treatment spinal stenosis discount persantine 100 mg on line. How does rhodopsin bleaching lead to action potentials traveling through the optical pathway Electrical signals in cells occur as a result of ion movement between the intracellular and extracellular compartments. In one surgical procedure for the disease, a drain is inserted to relieve pressure in the endolymph by removing some of the fluid. If that fails to provide relief, as a last resort the vestibular nerve can be severed. This surgery is difficult to perform, as the vestibular nerve lies near many other important nerves, including facial nerves and the auditory nerve. Patients who undergo this procedure are advised that the surgery can result in deafness if the cochlear nerve is inadvertently severed. Activated Opsin (bleached Activates transducin retinal pigment) 3 In the recovery phase, retinal recombines with opsin. Rod Tonic release of neurotransmitter onto bipolar neurons Neurotransmitter release decreases in proportion to amount of light. Depending on location in the retina, as many as 15 to 45 photoreceptors may converge on one bipolar neuron. Multiple bipolar neurons in turn innervate a single ganglion cell, so that the information from hundreds of millions of retinal photoreceptors is condensed down to a mere 1 million axons leaving the eye in each optic nerve. Convergence is minimal in the fovea, where some photoreceptors have a 1:1 relationship with their bipolar neurons, and greatest at the outer edges of the retina. Horizontal cells synapse with photoreceptors and bipolar cells to mediate lateral inhibition in the retina, the same phenomenon described for touch receptors earlier. Amacrine cells modulate information flowing between bipolar cells and ganglion cells. Bipolar Cells Glutamate release from photoreceptors onto bipolar neurons begins signal processing. By using different glutamate receptors, one stimulus (light) creates two different responses with a single neurotransmitter. Whether glutamate is excitatory or inhibitory depends on the type of glutamate receptor on the bipolar neuron. Rod Horizontal and amacrine cells influence communication at the rod-bipolar or bipolar-ganglion synapses. Bipolar cells are either activated or inhibited by light, depending on their type. Ganglion cells respond most strongly when there is good contrast of light intensity between the center and the surround. Visual Field Type On-center, off-surround Bright light onto center Field Is On-Center/Off-Surround Ganglion cell is excited by light in the center of the visual field. Field Is Off-Center/On-Surround Ganglion cell is inhibited by light in the center of the visual field. Off-center, on-surround Bright light onto surround Bright light onto surround Both field types Diffuse light on both center and surround Ganglion cell responds weakly. Bipolar cell signal processing is also modified by input from the horizontal and amacrine cells. Ganglion Cells Bipolar cells synapse with ganglion cells, the next neurons in the pathway. We know more about ganglion cells because they lie on the surface of the retina, where their axons are the most accessible to researchers. Extensive studies have been done in which researchers stimulated the retina with carefully placed light and evaluated the response of the ganglion cells. These areas, known as visual receptive fields, are similar to receptive fields in the somatic sensory system [p. Only a few photoreceptors are associated with each ganglion cell, and so visual acuity is greatest in these areas. Assume that two screens have the same number of "photoreceptors," as indicated by a maximal screen resolution of 1280 * 1024 pixels. If screen A has one photoreceptor becoming one "ganglion cell" pixel, the actual screen resolution is 1280 * 1024, and the image is very clear. If eight photoreceptors on screen B converge into one ganglion cell pixel, then the actual screen resolution falls to 160 * 128, resulting in a very blurry and perhaps indistinguishable image. This organization allows each ganglion cell to use contrast between the center and its surround to interpret visual information. Strong contrast between the center and surround elicits a strong excitatory response (a series of action potentials) or a strong inhibitory response (no action potentials) from the ganglion cell. If light is brightest in the off-surround region of the field, the on-center/off-surround field ganglion cell is inhibited and stops firing action potentials. Thus, the retina uses contrast rather than absolute light intensity to recognize objects in the environment. One advantage of using contrast is that it allows better detection of weak stimuli. Scientists have now identified multiple types of ganglion cells in the primate retina. The two predominant types, which account for 80% of retinal ganglion cells, are M cells and P cells. Large magnocellular ganglion cells, or M cells, are more sensitive to information about movement. Smaller parvocellular ganglion cells, or P cells, are more sensitive to signals that pertain to form and fine detail, such as the texture of objects in the receptive field. A recently discovered subtype of ganglion cell, the melanopsin retinal ganglion cell, apparently also acts as a photoreceptor to relay information about light cycles to the suprachiasmatic nucleus, which controls circadian rhythms [p. At this point, some nerve fibers from each eye cross to the other side of the brain for processing. Objects seen by both eyes fall within the binocular zone and are perceived in three dimensions. Objects seen with only one eye fall outside the binocular zone and are perceived in only two dimensions. The two eyes have slightly different views of objects in this region, and the brain processes and integrates the two views to create 10. Our sense of depth perception-that is, whether one object is in front of or behind another-depends on binocular vision. Objects that fall within the visual field of only one eye are in the monocular zone and are viewed in two dimensions. Most axons, however, project to the lateral geniculate body of the thalamus, where the optic fibers synapse onto neurons leading to the visual cortex in the occipital lobe. The lateral geniculate body is organized in layers that correspond to the different parts of the visual field, which means that information from adjacent objects is processed together. This topographical organization is maintained in the visual cortex, with the six layers of neurons grouped into vertical columns. Within each portion of the visual field, information is further sorted by form, color, and movement. The cortex merges monocular information from the two eyes to give us a binocular view of our surroundings. Information from on/off combinations of ganglion cells is translated into sensitivity to line orientation in the simplest pathways, or into color, movement, and detailed structure in the most complex. Each of these attributes of visual stimuli is processed through a separate pathway, creating a network whose complexity we are just beginning to unravel. Now check your understanding of this running problem by comparing your answers to those in the summary table. Anant was told about the surgical options but elected to continue medical treatment for a little longer. Q2: Subjective tinnitus occurs when an abnormality occurs somewhere along the anatomical pathway for hearing. The middle ear consists of malleus, incus, and stapes, bones that vibrate with sound. The hearing portion of the inner ear consists of hair cells in the fluid-filled cochlea. Integration and Analysis N/A Subjective tinnitus could arise from a problem with any of the structures named. Neural defects may cause the cochlear nerve to fire spontaneously, creating the perception of sound. If the floating crystals displace the cupula, the brain will perceive movement that is not matched to sensory information coming from the eyes. Reducing salt intake should also reduce the amount of fluid in the extracellular compartment because the body will retain less water. The ends of the semicircular canals contain sensory cristae, each crista consisting of a cupula with embedded hair cells. The primary symptom of positional vertigo is brief dizziness following a change in position. The vestibular nerve transmits information about balance and rotational movement from the vestibular apparatus to the brain. In this article, you explored sensory receptors in the human body and learned how each type is designed to enable us to perceive different aspects of the world around us. Despite the unique characteristics of each sense, basic patterns emerge for sensory transduction and perception. Molecular interactions between signal molecules and ion channels or G protein-coupled receptors initiate many sensory pathways. The brain processes and filters incoming signals, sometimes acting on sensory information without that information ever reaching conscious awareness. Many of the visceral reflexes you will study are unconscious responses to sensory input. Sensory stimuli are divided into the special senses of vision, hearing, taste, smell, and equilibrium, and the somatic senses of touch, temperature, pain, itch, and proprioception. Sensory pathways begin with a stimulus that is converted by a receptor into an electrical potential. If the stimulus is above threshold, action potentials pass along a sensory neuron to the central nervous system. Sensory receptors vary from free nerve endings to encapsulated nerve endings to specialized receptor cells. There are four types of sensory receptors, based on the stimulus to which they are most sensitive: chemoreceptors, mechanoreceptors, thermoreceptors, and photoreceptors. Each receptor type has an adequate stimulus, a particular form of energy to which it is most responsive. Multiple sensory neurons may converge on one secondary neuron and create a single large receptive field. Sensory information from the spinal cord projects to the thalamus, then on to the sensory areas of the cerebral cortex. The central nervous system is able to modify our level of awareness of sensory input. The perceptual threshold is the level of stimulus intensity necessary for us to be aware of a particular sensation. The modality of a signal and its location are indicated by which sensory neurons are activated. The association of a receptor with a specific sensation is called labeled line coding. Localization of auditory information depends on the timing of receptor activation in each ear. Lateral inhibition enhances the contrast between the center of the receptive field and the edges of the field. In population coding, the brain uses input from multiple receptors to calculate location and timing of a stimulus. Stimulus intensity is coded by the number of receptors activated and by the frequency of their action potentials. For tonic receptors, the sensory neuron fires action potentials as long as the receptor potential is above threshold. There are four somatosensory modalities: touch, proprioception, temperature, and nociception. Secondary sensory neurons cross the midline so that one side of the brain processes information from the opposite side of the body. Nociceptors are free nerve endings that respond to chemical, mechanical, or thermal stimuli. Some responses to irritants, such as the withdrawal reflex, are protective spinal reflexes. Referred pain from internal organs occurs when multiple primary sensory neurons converge onto a single ascending tract. Pain may be modulated either by descending pathways from the brain or by gating mechanisms in the spinal cord. Chemoreception is divided into the special senses of smell (olfaction) and taste (gustation). Olfactory sensory neurons in the nasal cavity are bipolar neurons whose pathways project directly to the olfactory cortex. Taste receptor cells are nonneural cells with membrane channels or receptors that interact with taste ligands.

Pituitary gonadotropes are necessary for the androgen-mediated inguinoscrotal phase at weeks 25­35 lanza ultimate treatment best buy persantine. The hypothalamic-pituitary-gonadal axis is important for testosterone production as axis anomalies lead to androgen deficiency manifested as micropenis and cryptorchidism treatment as prevention purchase persantine 100mg. Interestingly medications or drugs 100 mg persantine overnight delivery, bilateral undescended testicles are seen in subgroups with high gonadotropes treatment atrial fibrillation buy 25 mg persantine amex, suggesting a lack of negative feedback from androgens treatment 2015 persantine 100 mg for sale. Males with androgen insensitivity syndrome have intraabdominal testes positioned near the internal inguinal ring [33]. This provides evidence for androgen signaling being involved in the second phase of testicular descent. Contraction may be important to orient the gubernacular tip toward the scrotum and assist in migration [35]. In E17 mice, an increase in contraction is observed and lasts through the first postnatal week. Formation of the Genital Tubercle Interestingly, the initial fating and source of the genital mesenchyme is not well understood. Only Wnt5a mouse mutants that fail to form genital swellings have been used to study early genital tubercle development [37]. In these mice, the endodermal urorectal septum fails to contact the cloacal ectoderm and therefore the cloacal membrane fails to form [37]. Thus, the cloacal membrane is required for development of the genital swellings and therefore the genital tubercle. Experts postulate that a diffusible signal likely emanates from the cloacal membrane to spatiotemporally specify the early genital mesenchyme. Similar to a limb, the majority of the genital tubercle is composed of mesoderm wrapped with an ectodermal covering. This ectodermal covering is required for proximodistal patterning and maintenance of outgrowth of the genital tubercle. Removal of this epithelium results in stage-dependent truncation of the baculum and erectile tissues [39]. Furthermore, the only structural distinction of the dorsoventral axis is the urethral plate. Therefore, the urethral plate has been suspected to be the organizing center of the genital tubercle. Based on experiments where the urethral plate, which was transplanted to the anterior surface of a developing limb, was competent to induce mirror-imaged digits and muscle tissue from the mesenchyme, the urethral plate was identified as an organizing region with the potential to induce tissue polarity and tubulognesis [38]. Importantly, this organizing function has been demonstrated only in the limb and not in the genital tubercle itself [36]. Formation of the Urethra the urethral plate forms from an extension of the cloacal endoderm. Past theories of dual origin urethral ontogeny have been disproven; lineage studies have demonstrated that the entire proximal and distal urethra is formed by an endodermal urethral plate, not an ingrowth of the ectoderm [39a]. The urethra and urethral plate have been investigated extensively regarding tubulogenesis, that is, urethral closure. Several genetic pathways have been implicated including Shh, Fgf10-Fgfr2, EphB2-EphrinB2, Hoxa13, and Dlx5/6. Urethral closure occurs at E16 when the proximal urethral plate edges fuse, forming a lumen; this process progresses to the glans at E18 when the lumen opens on the glans [40]. Two processes are required for urethral closure: ventrolateral growth of the preputial swellings and remodeling of the bilaminar urethral plate into a tube. The phenotypic result of failure of either of these two processes is hypospadias (described in detail later in the chapter). These processes are tightly controlled with regards to a fine balance between proliferation and apoptosis. Differentiation of the Male and Female Genitalia the external genitalia remains gender-neutral until approximately E15 in the mouse. Female versus male phenotype is governed by the balance of androgens and estrogens. It was previously thought that a default feminine genital phenotype existed, resulting in development of a clitoris, labia majora and minora, a urethral orifice posterior to the clitoris in the midline, and a separate, distinct vaginal introitus posterior to the urethra in the midline. Alternatively, increased androgen signaling in a female increases the estrogen:androgen ratio, resulting in genital tubercle elongation, complete tubularization of the urethra with some degree of labioscrotal fold fusion resulting in clitoromegaly or a pseudophallus, an orifice on the enlarged clitoris or pseudophallus, and a single perineal opening that branches to the urethra and vagina. Decreased androgenization of the male increases the estrogen:androgen ratio, resulting in feminization of the male genitalia: a smaller genital tubercle, incomplete formation of the urethra, and incomplete fusion of the preputial folds, resulting in micropenis, hypospadias, and incomplete foreskin. These states of abnormal androgenization result in a phenotype of ambiguous genitalia. Genetic Control of External Genitalia Ontogeny Several genes have been described as important in the development of the external genitalia. Homeobox 13 (Hox13) Hox13 isoforms have dual roles in the development of the genital tubercle: an early role in the genital mesenchyme and a later role in urethral tube closure. Hoxa13 and Hoxd13 are expressed during outgrowth of the genital tubercle as well as the urethral plate and surrounding mesenchyme [42­44]. Homozygous deletion of either Hox13 isoform creates genital tubercle patterning defects; double knockout for both Hoxd13 and Hoxa13 develop aphallia [45, 46]. Fibroblast Growth Factors (Fgfs) In limb outgrowth, T-box transcription factors control Fgf expression during limb outgrowth [47]. Similarly, expression of Tbx2, Tbx3, Tbx4, and Tbx5 have been described in the genitalia but have not been found as required during genital development [36, 48]. No clear role for Fgf ligands has been shown in initiation or maintenance of genital tubercle outgrowth. While Fgf8 and Shh function in a positive feedback loop to complete limb outgrowth and patterning, no such role has been found in the genital tubercle. A role for only Fgf10, which binds the Fgfr2 receptor, is described as necessary for urethral tube closure [49, 50]. Fgf10 is expressed in the genital tubercle mesenchyme adjacent to the urethral cells. The interaction of the ligand with the Fgfr2 receptor is required for ventral growth of the preputial folds and formation of the complete foreskin [49]. Additionally, conditional loss of the Fgfr2 receptor from the ectoderm results in severe hypospadias and loss of the ventral prepuce while conditional loss of Fgfr2 from the endoderm causes mild hypospadias [49, 51, 52]. Further studies where knockouts can be controlled both spatially and temporally will be required to dissect the role of the Fgf in development of the external genitalia. Currently, Fgf signaling is required for mesenchymal outgrowth on the ventral surface and urethral maturation and closure. The importance of Wnt signaling is further supported by the fact that conditional -Catenin knockouts do not have external genitalia [53]. Initiation of the paired genital swellings does occur in these mutants, suggesting that canonical Wnt signaling is required for initiation and/ or maintenance of genital outgrowth. Interestingly, the loss of -Catenin expression reduces the expression of cellular pathway gene expression, including Shh. Further evidence for the importance of canonical Wnt signaling abounds: (1) loss of Lrp6, a coreceptor of canonical Wnt signaling, mimics this phenotype, and (2) target genes of canonical Wnt signaling, such as Dkk1, are expressed in the distal urethral epithelium [54, 55]. In contrast, there is no clear role for noncanonical Wnt signaling via Wnt5a and Wnt11 in the genital tubercle. Loss of Wnt5a demonstrates a variable phenotype ranging from shortened to normal-sized genital tubercles [37, 56]. Similarly, loss of a noncanonical Wnt signaling receptor Ror2 results in an underdeveloped genital tubercle [57]. Finally, despite proper spatiotemporal expression patterns of another noncanonical Wnt, Wnt11, no clear role could be distinguished [58]. Noncanonical Wnt signaling may play a role in maintenance of genital tubercle outgrowth. Sonic Hedgehog (Shh) Sonic hedgehog (Shh) is expressed in the cloacal endoderm prior to genital budding and persists in the urethral epithelium during outgrowth [37, 38, 50]. Though Shh knockouts do not develop a genital tubercle, the paired genital swellings do form, suggesting that Shh signaling is important in initiation and/or maintenance of genital outgrowth [38, 50]. Interestingly, the loss-of-Shh phenotype can be partially rescued by -Catenin overexpression in the urethral epithelium [53]. Time-dependent conditional knockout models have demonstrated the intricate role of Shh [37, 53]. It is both a proliferative cue for the elongating mesenchyme as well as an inhibitor of apoptosis of the ectoderm. To understand where Shh acts, conditional deletions of Smoothened (Smo), a coreceptor required for Shh intracellular transduction pathways, have been performed [37, 53]. Deletion from the ectoderm epithelial cap or the mesenchyme, but not the urethral epithelium, disrupts genital tubercle formation. When removed from the mesenchyme, the genital tubercle is shortened and has a hypospadic phenotype. Therefore, Shh is required for integration of the mesoderm and ectoderm to form a normal phallus: it is a proliferative and antiapoptotic signal for both the mesenchyme and the ectoderm. Expression is identical in male and female embryos until E12 [60]; thereafter, expression is localized to the ventral surface to mediate urethral plate growth and closure [59]. This mutation results in external genitalia that are indistinguishable from female mice. Additional evidence from deletion of 5-alpha reductase, an enzyme converting testosterone to the more active androgen dihydrotestosterone, results in a range of phenotypes from hypospadias to micropenis to complete feminization [61]. Multiple surgeries are, however, often required, increasing the risk for surgical complications as well as sexual dysfunction and psychological problems. We will explore the genetics of the two most common disorders of sexual development, hypospadias and cryptorchidism, in further detail. Hypospadias Hypospadias is a condition in which the urethral meatus opens more proximally on the penile shaft. Hypospadias is one of the most common genitourinary birth defects, occurring in $1 in 300 male births. Interestingly its incidence is increasing, suggesting that environmental cues may have an effect. Hypospadias is commonly associated with incomplete foreskin and chordee, a ventral curvature of the penis. The urethral meatus can be located at the glans in the mildest of phenotypes, or as proximal as the scrotum in more severe cases. Correction requires surgical repair, sometimes in multiple stages, and is associated with significant morbidity. It can be associated with long-term urinary difficulties, difficulty with sexual activity and fertility in the future, and decreased quality of life [64, 65]. Though not fully elucidated, the etiology of hypospadias is thought to be multifactorial, with hormonal, environmental, and genetic factors. One study found that the incidence of hypospadias in monochorionic twins is 4% while only 1% in dichorionic twins [66]. Prematurity and low birth weight are also strongly associated with hypospadias [67]. Many genes have been implicated in being associated with hypospadias due to changes in both steroidogenic and nonsteroidogenic processes involved in genital tubercle development. Mutations in genes involved in the development of the urogenital system can potentially lead to hypospadias. Fgf10 and Fgfr2 deficient mice have also been shown to develop hypospadias due to cell proliferation arrest and premature maturation of the urethral epithelium [28, 70, 71]. The Wnt/-catenin pathway has also been implicated as a sexually dimorphic gene that may be involved in the development of hypospadias. Several candidate genes for hypospadias have been identified through genome-wide association studies. Defects in the androgen receptor have also been implicated as well as defects in 5 alpha reductase [74, 75]. Given the interplay between estrogen and androgens in the developing genitourinary tract, defects in the estrogen receptor have been investigated, and also found in a metaanalysis to be associated with an increased risk of hypospadias [76]. Sex chromosome abnormalities are highly associated with hypospadias development, but further studies are needed to fully explore the regions of the sex chromosomes that are important in genital development [79]. Vamp7, a vesicle trafficking protein located on Xq28, has been verified as having a role in hypospadias. Anogenital distance has been evaluated elsewhere as a marker for androgen exposure in humans [81]. Shorter anogenital distances have been linked with decreased testosterone levels, decreased semen quality, and lower fertility. This increase in estrogenic and decrease in androgenic activity contributes to the phenotypes associated with Vamp7. For example, transgenic mice had decreased testis size and decreases in spermatogenesis. It is one of the most common congenital anomalies, occurring in 1%­9% of boys worldwide [82]. While most of these cases will spontaneously descend within the first 3 months, 1% of boys are still cryptorchid by the first year of age. The primary treatment for cryptorchidism is surgical intervention called an orchidopexy. Descent of the testicles is important for proper testicular function due to the temperature difference between the body and the scrotum. Any history of cryptorchidism makes one 3­4 times more likely to develop testicular cancer.

Hyperkalemia can lead to dangerous cardiac arrhythmias because elevated [K +] depolarizes cells medications that cause high blood pressure persantine 100mg on-line. At maximal exertion medicine 3202 cheap 25mg persantine mastercard, the ability of the cardiovascular system to deliver oxygen and nutrients appears to be the primary limiting factor medicine 627 buy persantine 25 mg lowest price. Glucose can be metabolized through both oxidative and anaerobic pathways treatment 02 binh persantine 100 mg order line, but fatty acid metabolism requires oxygen symptoms job disease skin infections discount persantine 100 mg visa. Glucagon, cortisol, catecholamines, and growth hormone influence glucose and fatty acid metabolism during exercise. Plasma glucose concentrations rise with exercise, but insulin secretion decreases. This response reduces glucose uptake by most cells, making more glucose available for exercising muscle. Exercise hyperventilation results from feedforward signals from the motor cortex and sensory feedback from peripheral sensory receptors. Cardiac output increases with exercise because of increased venous return and sympathetic stimulation of heart rate and contractility. Blood flow through exercising muscle increases dramatically when skeletal muscle arterioles dilate. The baroreceptors that control blood pressure change their setpoints during exercise. Heat released during exercise is dissipated by sweating and increased cutaneous blood flow. Physical activity can help prevent or decrease the risk of developing high blood pressure, strokes, and type 2 diabetes mellitus. Studies suggest that serotonin release during exercise may help alleviate depression. When exercise begins, feedforward responses prevent significant disruption of homeostasis. Name the two muscle compounds that store energy in the form of high-energy phosphate bonds. What is meant by the term oxygen deficit, and how is it related to excessive postexercise oxygen consumption Which two thermoregulatory mechanisms are triggered by this change in temperature during exercise Compare and contrast each of the terms in the following sets of terms, especially as they relate to exercise: a. Specify whether each of the following parameters stays the same, increases, or decreases when a person becomes better conditioned for athletic activities: a. Concept map: Map the metabolic, cardiovascular, and respiratory changes that occur during exercise. Include the signals to and from the nervous system, and show what specific areas signal and coordinate the exercise response. What causes insulin secretion to decrease during exercise, and why is this decrease adaptive Diagram the three theories that explain why the normal baroreceptor reflex is absent during exercise. List and briefly discuss the benefits of a lifestyle that includes regular exercise. You have decided to manufacture a new sports drink that will help athletes, from football players to gymnasts. List at least four different ingredients you would include in your drink, and indicate why each is important for the athlete. The following graph shows left ventricular pressure-volume curves in one individual. Which exercise curve shows an increase in stroke volume due primarily to increased contractility Which exercise curve shows an increase in stroke volume due primarily to increased venous return Mechanistically, why did the end-diastolic volume in curve C fall back toward the resting value Amanda Peterson Beadle, Teen Pregnancies Highest in States with Abstinence-Only Policies, April 10, 2012. Positive and negative feedback Flagella Steroids Agonist/antagonist Up- and down-regulation Prostaglandins Hypothalamic-pituitary axis Prolactin Oxytocin Spinal reflex Hot flashes 26. This scenario actually happens to a small number of men who have a condition known as pseudohermaphroditism pseudes, false + hermaphrodites, the dual-sex offspring of Hermes and Aphrodite. These men have the internal sex organs of a male but inherit a gene that causes a deficiency in one of the male hormones. Consequently, they are born with external genitalia that appear feminine, and they are raised as girls. At puberty pubertas, adulthood, the period when a person makes the transition from being nonreproductive to being reproductive, individuals with pseudohermaphroditism begin to secrete more male hormones. Not surprisingly, a conflict arises: Should these individuals change gender or remain female Reproduction is one area of physiology in which we humans like to think of ourselves as significantly advanced over other animals. We mate for pleasure as well as procreation, and women are always sexually receptive. Like many other terrestrial animals, humans have internal fertilization that allows motile flagellated sperm to remain in an aqueous environment. To facilitate the process, we have mating and courtship rituals, as do other animals. Development is also internal, within the uterus, which protects the growing embryo from dehydration and cushions it in a layer of fluid. Humans are sexually dimorphic di-, two + morphos, form, meaning that males and females are physically distinct. This distinction is sometimes blurred by dress and hairstyle, but these are cultural acquisitions. Everyone agrees that male and female humans are physically dimorphic, but we are still debating just how behaviorally and psychologically dimorphic we are. Sex hormones play a significant role in the behavior of other mammals, acting on adults as well as influencing the brain of the developing embryo. Human fetuses are exposed to sex hormones while in the uterus, but it is unclear how much influence these hormones have on behavior later in life. Does the preference of little girls for dolls I and of little boys for toy guns have a biological basis or a cultural basis We have no answer yet, but growing evidence suggests that at least part of our brain structure is influenced by sex hormones before we ever leave the womb. The topic is an incredibly complex one, with numerous hormones, cytokines, and paracrine signal molecules interacting in constantly shifting interplay. Because of the complexity of the topic, this chapter presents only a generalized overview. We begin our discussion with gametes that fuse to form the fertilized egg, or zygote. But one thing is missing: After seven years of marriage, they have been unable to have a child. She begins her workup of Kate and Jon by asking detailed questions about their reproductive histories. Based on the answers to these questions, she will then order tests to pinpoint the problem. Gonads gonos, seed are the organs that produce gametes gamein, to marry, the eggs and sperm that unite to form new individuals. The male gonads are the testes (singular testis), which produce sperm (spermatozoa). The undifferentiated gonadal cells destined to produce eggs and sperm are called germ cells. The internal genitalia consist of accessory glands and ducts that connect the gonads with the outside environment. The 22 pairs of autosomal chromosomes in our cells direct development of the human body form and of variable characteristics such as hair color and blood type. The two sex chromosomes, designated as either X or Y, contain genes that direct development of internal and external sex organs. The X chromosome is larger than the Y chromosome and includes many genes that are missing from the Y chromosome. Eggs and sperm are haploid (1n) cells with 23 chromosomes, one from each of the 22 matched pairs plus one sex chromosome. When egg and sperm unite, the resulting zygote then contains a unique set of 46 chromosomes, with one chromosome of each matched pair coming from the mother and the other from the father. Once the ovaries develop in a female fetus, one X chromosome in each cell of her body is inactivated and condenses into a clump of nuclear chromatin known as a Barr body. Because inactivation occurs early in development-before cell division is complete-all cells of a given tissue will usually have the same active X chromosome, either maternal or paternal. Before differentiation, the embryonic tissues are considered bipotential because they cannot be morphologically identified as male or female. Under the influence of the appropriate developmental signal (described later), the medulla will develop into a testis. The bipotential internal genitalia consist of two pairs of accessory ducts: Wolffian ducts (mesonephric ducts) derived from the embryonic kidney, and Müllerian ducts (paramesonephric ducts). These structures differentiate into the male and female reproductive structures as development progresses. Wolffian duct forms epididymis, vas deferens, and seminal vesicle (testosterone present). Bipotential stage (6-week embryo) Wolffian (mesonephric) duct Testis Müllerian duct Wolffian duct Uterus At birth Ovary 3 Absence of antiMüllerian hormone allows the Müllerian duct to become the Fallopian tube, uterus, and upper part of the vagina. At birth Prostate Fallopian tube (from Müllerian duct) Uterus Testis Vagina Epididymis Seminal vesicle Vas deferens 3 Testosterone from testis converts Wolffian duct into seminal vesicle, vas deferens, and epididymis. At birth At birth Glans penis Labium majus Labium minus Clitoris Urethral opening Vaginal opening Scrotum Anus Anus 2 the testes descend from the abdominal cavity into the scrotum. However, many genes on the X chromosome, called X-linked genes, have no matching gene on the much smaller Y chromosome. Females always get two copies of X-linked genes, so the expression of X-linked traits follows the usual pattern of gene dominance and recessiveness. Males, however, receive only one copy of an X-linked gene-on the X chromosome from their mother-so males always exhibit the traits associated with an X-linked gene. One controversial aspect of the masculinizing effects of testosterone is its influence on human sexual behavior and gender identity. It is well documented that in many nonhuman mammals, adult sexual behavior depends on the absence or presence of testosterone during critical periods of brain development. In human behavior, it is very difficult to separate biological influences from environmental factors, and it will probably be years before this question is resolved. Research indicates that female development is more complex than originally thought, with 26 multiple genes required for the development of functional ovaries. Note that testicular development does not require male sex hormones such as testosterone. The developing embryo cannot secrete testosterone until after the gonads differentiate into testes. Once the testes differentiate, they begin to secrete three hormones that influence development of the male internal and external genitalia. Both bind to the same androgen receptor, but the two ligands elicit different responses. Testosterone converts the Wolffian ducts into male accessory structures: epididymis, vas deferens, and seminal vesicle (male 3). Later in fetal development, testosterone controls migration of the testes from the abdomen into the scrotum, or scrotal sac. At birth, the infants with pseudohermaphroditism appear to be female and are raised as such. If the testes are removed from an early male embryo, why does it develop a uterus and Fallopian tubes rather than the normal male accessory structures Traditionally, sex determination has been based on appearance of the external genitalia at birth, but the idea that individuals should be allowed to choose their sex when they become old enough is gaining ground. They are the only flagellated cells in the body and are highly motile so that they can swim up the female reproductive tract in their search for an egg to fertilize. The timing of gamete production, or gametogenesis, is also very different in males and females. Most evidence indicates that women are born with all the eggs, or oocytes, they will ever have. During the reproductive years, eggs mature in a cyclic pattern and are released from the ovaries roughly once a month. Men, in contrast, manufacture sperm continuously from the time they reach reproductive maturity. In both sexes, germ cells in the embryonic gonads first undergo a series of mitotic divisions to increase their numbers 1. After that, the germ cells are ready to undergo meiosis, the cell division process that forms gametes. Instead, each duplicated chromosome forms two identical sister chromatids, linked together at a region known as the centromere. The primary gametes are then ready to undergo meiotic divisions to create haploid cells.

Explain the relationship between the lungs treatment for vertigo buy generic persantine 25mg on line, the pleural membranes administering medications 8th edition 25 mg persantine buy otc, the pleural fluid symptoms influenza buy persantine 25mg without a prescription, and the thoracic cage symptoms zenkers diverticulum order genuine persantine. If vital capacity decreases with age but total lung capacity does not change symptoms 2 months pregnant 25 mg persantine mastercard, which lung volume must be changing Inspiration Occurs When Alveolar Pressure Decreases For air to move into the alveoli, pressure inside the lungs must become lower than atmospheric pressure. During inspiration, thoracic volume increases when certain skeletal muscles of the rib cage and diaphragm contract. Contraction of the diaphragm causes between 60% and 75% of the inspiratory volume change during normal quiet breathing. Rib movement during inspiration has been likened to a pump handle lifting up and away from the pump (the ribs moving up and away from the spine) and to the movement of a bucket handle as it lifts away from the side of a bucket (ribs moving outward in a lateral direction). For many years, quiet breathing was attributed solely to the action of the diaphragm and the external intercostal muscles. It was thought that the scalenes and sternocleidomastoid muscles were active only during deep breathing. In recent years, however, studies have changed our understanding of how these accessory muscles contribute to quiet breathing. Observation of patients with neuromuscular disorders has revealed that although the contracting diaphragm increases thoracic volume by moving toward the abdominal cavity, it also tends to pull the lower ribs inward, working against inspiration. In normal individuals, we know that the lower ribs move up and out during inspiration rather than inward. The fact that there is no up-and-out rib motion in patients with paralyzed scalenes tells us that normally the scalenes must be contributing to inspiration by lifting the sternum and upper ribs. New evidence also downplays the role of the external intercostal muscles during quiet breathing. However, the external intercostals play an increasingly important role as respiratory activity increases. Because the exact contribution of external intercostals and scalenes varies depending on the type of breathing, we group these muscles together and simply call them the inspiratory muscles. Vital capacity represents the maximum amount of air that can be voluntarily moved into or out of the respiratory system with one breath. Other capacities of importance in pulmonary medicine include the inspiratory capacity (tidal volume + inspiratory reserve volume) and the functional residual capacity (expiratory reserve volume + residual volume). During Ventilation, Air Flows because of Pressure Gradients Breathing is an active process that requires muscle contraction. Air flows into the lungs because of pressure gradients created by a pump, just as blood flows because of the pumping action of the heart. In the respiratory system, muscles of the thoracic cage and diaphragm function as the pump because most lung tissue is thin exchange epithelium. When these muscles contract, the lungs expand, held to the inside of the chest wall by the pleural fluid. The primary muscles involved in quiet breathing (breathing at rest) are the diaphragm, the external intercostals, and the scalenes. During forced breathing, other muscles of the chest and abdomen may be recruited to assist. Examples of physiological situations in which breathing is forced include exercise, playing a wind instrument, and blowing up a balloon. As we noted earlier in the chapter, air flow in the respiratory tract obeys the same rule as blood flow: Flow P/R this equation means that (1) air flows in response to a pressure gradient (P) and (2) flow decreases as the resistance (R) of the system to flow increases. Movement of the handle on a hand pump is analogous to the lifting of the sternum and ribs. Sternum Front view: "Bucket handle" motion increases lateral dimension of rib cage. The bucket handle moving up and out is a good model for lateral rib movement during inspiration. Negative numbers designate subatmospheric pressures, and positive numbers denote higher-thanatmospheric pressures. Time 0 In the brief pause between breaths, alveolar pressure is equal to atmospheric pressure (0 mm Hg at point A1). Time 0­2 sec: Inspiration As inspiration begins, inspiratory muscles contract, and thoracic volume increases. With the increase in volume, alveolar pressure falls about 1 mm Hg below atmospheric pressure (-1 mm Hg, point A2), and air flows into the alveoli (point C 1 to point C 2). Because the thoracic volume changes faster than air can flow, alveolar pressure reaches its lowest value about halfway through inspiration (point A2). As air continues to flow into the alveoli, pressure increases until the thoracic cage stops expanding, just before the end of inspiration. Air movement continues for a fraction of a second longer, until pressure inside the lungs equalizes with atmospheric pressure (point A3). At the end of inspiration, lung volume is at its maximum for the respiratory cycle (point C 2), and alveolar pressure is equal to atmospheric pressure. You can demonstrate this phenomenon by taking a deep breath and stopping the movement of your chest at the end of inspiration. This exercise shows that at the end of inspiration, alveolar pressure is equal to atmospheric pressure. When lung volume is at its minimum, alveolar pressure is and external intercostal muscle contraction is. Expiration Occurs When Alveolar Pressure Increases At the end of inspiration, impulses from somatic motor neurons to the inspiratory muscles cease, and the muscles relax. Elastic recoil of the lungs and thoracic cage returns the diaphragm and rib cage to their original relaxed positions, just as a stretched elastic waistband recoils when released. Because expiration during quiet breathing involves passive elastic recoil rather than active muscle contraction, it is called passive expiration. Alveolar pressure is now higher than atmospheric pressure, so air flow reverses and air moves out of the lungs. At the end of expiration, air movement ceases when alveolar pressure is again equal to atmospheric pressure (point A5). At this point, the respiratory cycle has ended and is ready to begin again with the next breath. During exercise or forced heavy breathing, these values become proportionately larger. Active expiration occurs during voluntary exhalations and when ventilation exceeds 30­40 breaths per minute. When they contract, they pull the ribs inward, reducing the volume of the thoracic cavity. Forcefully blow as much air out of your lungs as you can, noting the movement of your hands as you do so. Abdominal contraction pulls the lower rib cage inward and decreases abdominal volume, actions that displace the intestines and liver upward. The displaced viscera push the diaphragm up into the thoracic cavity and passively decrease chest volume even more. The action of abdominal muscles during forced expiration is why aerobics instructors tell you to blow air out as you lift your head and shoulders during abdominal "crunches. Any neuromuscular disease that weakens skeletal muscles or damages their motor neurons can adversely affect ventilation. In addition, loss of the ability to cough increases the risk of pneumonia and other infections. Examples of diseases that affect the motor control of ventilation include myasthenia gravis [p. Intrapleural Pressure Changes during Ventilation Ventilation requires that the lungs, which are unable to expand and contract on their own, move in association with the expansion and relaxation of the thorax. As we noted earlier in this chapter, the lungs are enclosed in the fluid-filled pleural sac. The surface of the lungs is covered by the visceral pleura, and the portion of the sac that lines the thoracic cavity is called the parietal pleura paries, wall. Cohesive forces of the intrapleural fluid cause the stretchable lung to adhere to the thoracic cage. Subatmospheric Intrapleural Pressure the intrapleural pressure in the fluid between the pleural membranes is normally subatmospheric. This subatmospheric pressure arises during fetal development, when the thoracic cage with its associated pleural membrane grows more rapidly than the lung with its associated pleural membrane. The two pleural membranes are held together by the pleural fluid bond, so the elastic lungs are forced to stretch to conform to the larger volume of the thoracic cavity. The combination of the outward pull of the thoracic cage and inward recoil of the elastic lungs creates a subatmospheric intrapleural pressure of about -3 mm Hg. You can create a similar situation by half-filling a syringe with water, removing all air, and capping the end with a plugged-up needle or three-way valve. Will she be more successful by taking a deep breath and holding it or by blowing all the air out of her lungs Why would loss of the ability to cough increase the risk of respiratory infections The bond holding the lung to the chest wall is broken, and the lung collapses, creating a pneumothorax (air in the thorax). P = Patm Knife Air Pleural fluid Visceral pleura Parietal pleura Lung collapses to unstretched size. Pleural membranes Diaphragm Elastic recoil of the chest wall tries to pull the chest wall outward. Play Phys in Action @Mastering Anatomy & Physiology Elastic recoil of lung creates an inward pull. As you pull on the plunger, the volume inside the barrel increases very slightly, but the cohesive forces between the water molecules cause the water to resist expansion. The pressure inside the barrel, which was initially equal to atmospheric pressure, decreases slightly as you pull on the plunger. If you release the plunger, it snaps back to its resting position, restoring atmospheric pressure inside the syringe. This experiment demonstrates the cohesive forces of water: water will resist being "stretched. In real life, this might happen with a knife thrust between the ribs, a broken rib that punctures the pleural membrane, or any other event that breaks the seal of the pleural cavity. Air moves down pressure gradients, so opening the pleural cavity to the atmosphere allows air to flow into the cavity, just as air enters a vacuum-packed can when you break the seal with a can opener. Air entering the pleural cavity breaks the fluid bond holding the lung to the chest wall. This condition, called pneumothorax 5 pneuma, air + thorax, chest 6, results in a collapsed lung that is unable to function normally. Pneumothorax can be due to trauma but can also occur spontaneously when a congenital bleb, a weakened section of lung tissue, ruptures, allowing air from inside the lung to enter the pleural cavity. Correction of a pneumothorax has two components: removing as much air from the pleural cavity as possible with a suction pump, and sealing the hole to prevent more air from entering. Any air remaining in the cavity is gradually absorbed into the blood, restoring the pleural fluid bond and reinflating the lung. Intrapleural Pressure during the Respiratory Cycle Pressures in the pleural fluid vary during a respiratory cycle. As inspiration proceeds, the pleural membranes and lungs follow the expanding thoracic cage because of the pleural fluid bond, but the elastic lung tissue resists being stretched. You can pull the plunger out a small distance without much effort, but the cohesiveness of the water makes it difficult to pull the plunger out any farther. The increased amount of work you do trying to pull the plunger out is paralleled by the work your inspiratory muscles must do when they contract during inspiration. During exercise or other powerful inspirations, intrapleural pressure may reach -8 mm Hg or lower. The lungs are released from their stretched position, and the intrapleural pressure returns to its normal value of about -3 mm Hg (point B3). Notice that intrapleural pressure never equilibrates with atmospheric pressure because the pleural cavity is a sealed compartment. A person has periodic spastic contractions of the diaphragm, otherwise known as hiccups. A stabbing victim is brought to the emergency room with a knife wound between the ribs on the left side of his chest. Lung Compliance and Elastance May Change in Disease States Pressure gradients required for air flow are created by the work of skeletal muscle contraction. The two factors that have the greatest influence on the amount of work needed for breathing are the stretchability of the lungs and the resistance of the airways to air flow. Most of the work of breathing goes into overcoming the resistance of the elastic lungs and the thoracic cage to stretching. Compliance refers to the amount of force that must be exerted on a body to deform it. In the lung, we can express compliance as the change of volume (V) that results from a given force or pressure (P) exerted on the lung: V/ P. A high-compliance lung stretches easily, just as a compliant person is easy to persuade. A low-compliance lung requires more force from the inspiratory muscles to stretch it. Compliance is the reciprocal of elastance (elastic recoil), the ability to resist being deformed. Elastance also refers to the ability of a body to return to its original shape when a deforming force is removed. A lung that stretches easily (high compliance) has probably lost its elastic tissue and will not return to its resting volume when the stretching force is released (low elastance). After many washings the elastic waistband is easy to stretch (high compliance) but lacking in elastance, making it impossible for the shorts to stay up around your waist.

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Because its absence only affected the thickening of the coelomic epithelium symptoms 10 days post ovulation order 100mg persantine free shipping, it clearly points out that its main action is to maintain the genital ridge by preventing its regression [81] medicine for high blood pressure purchase genuine persantine on line. Its presence also correlated to reduced Egfr gene expression and therefore prevented active proliferation of gonadal cells [24] symptoms 16 weeks pregnant buy generic persantine 100 mg line. A Pbx1 knockout mice study showed a range of anomalies during urogenital development: lack of adrenal glands and gonads treatment kitty colds cheap 25mg persantine free shipping, impaired differentiation of the mesonephros and kidneys symptoms your having a boy order 25 mg persantine, and the absence of the M llerian duct [109]. Molecular examination u showed that expression of Sf1 was dramatically reduced in Pbx1 mutants [109]. All the member genes of the Six family encode for transcription factors that carry the characteristic Six domains and homeodomains. In fact, these family members are functionally redundant to each other during mouse embryonic development with their overlapping tissue expression and equivalent binding to downstream target gene, for example, Mef3 for transactivation [111­113]. In contrast, Six4 single-knockout embryos demonstrated normal kidney formation [115]. Specifically, Six1 and Six4 showed an overlapping expression pattern in the coelomic epithelium of the forming genital ridges. These results suggested that Six1/Six4 simultaneously regulated genital ridge development and testicular development. A mechanistic study identified Fog2 and Sf1 as two downstream targets of Six1/Six4. Taken together, the Six1-Six4Fog2 trio is required for precise spatiotemporal regulation of Sry expression to ensure normal sex differentiation. Also, the Six1-Six4-Sf1 trio is critical to controlling the initial growth of gonad precursor cells and subsequent determination of gonad size. However, we cannot rule out the possibility that these genes might also be important regulators for spatiotemporal patterning of gonadal development. While the evidence for Hox genes in gonadogenesis is limited, a bunch of studies clearly identified their roles in sex differentiation. Morphologically, Hoxa10-deficient male mice showed bilateral cryptorchidism with decreased seminiferous tubule formation and disrupted spermatogenesis. Normal ovulatory cycles retained in mutant females suggest that Hoxa10 is not required for gonadal development in females. Further studies on Hoxa10 mutants have demonstrated that the reduced fertility in females should be caused by homeotic transformation of the anterior part of the oviduct into uterus [126]. The cause for female sterility is also a defective uterine environment without any defects in ovulation. As for male sterility, homeotic transformation from the vas deferens to an epididymis with an abnormal testis development is regarded as the cause. All similar phenotypes further identified the consistent roles of Hoxa10 and Hoxa11 in sex differentiation. Finally, Hoxa13-null mice showed agenesis of the distal portion of the M llerian ducts, indicating a role for Hoxa13 u not only in differentiation but also in the formation of M llerian ducts [127]. There are some suggested regulatory roles of Hoxa11, Hoxa10, and Hoxa13 in sex differentiation [124, 127, 130­132]. Loss of Hoxa13 in mice induces the loss of Bmp7 and Fgf8 signaling in the developing genital tubercle, which causes hypospadias [127]. Conditional overexpression remains the only research strategy to justify the statement. Gonad development and subsequent sex differentiation are well-coordinated complex processes that involve the participation of homeodomain proteins. Thus, further study on additional homeodomain proteins may reveal new insights that finally can contribute to human urogenital diseases. The subsequent formation of these steroidogenic tissues will promote appropriate hormonal signals for the development of the whole reproductive system and maintain the subsequent gender identity. Sry was expressed early in the indifferent gonad, spreading outward from the center to unlock the expression of Sox9, which will define the Sertoli lineage essential for male-specific differentiation, including formation of the sex cord and testis vasculature. In contrast, the absence in Sry expression as in female gonads bypassed the formation of these structures wherein the germ cells enter meiotic division to form the oogonia. Finally, various homeodomain proteins are expressed early during gonad formation, either to regulate the above processes or be involved in defining the structural integrity of developing organs in the reproductive system. References [1] Doitsidou M, Reichman-Fried M, Stebler J, Kprunner M, Drries J, Meyer D, et al. Developmental expression of mouse steroidogenic factor-1, an essential regulator of the steroid hydroxylases. Adrenal development is initiated by Cited2 and Wt1 through modulation of Sf-1 dosage. The presence of a common embryonic blastema for ovarian and testicular parenchymal (follicular, interstitial and tubular) cells in cattle Bos taurus. Mechanism of the eukaryotic chaperonin: protein folding in the chamber of secrets. Pleiotrophin and midkine, a family of mitogenic and angiogenic heparin-binding growth and differentiation factors. Molecular cloning and characterization of a transcription factor for the C-type natriuretic peptide gene promoter. The effect of stathmin phosphorylation on microtubule assembly depends on tubulin critical concentration. Loss of anchorage primarily induces nonapoptotic cell death in a human mammary epithelial cell line under atypical focal adhesion kinase signaling. A role for intracellular calcium downstream of G-protein signaling in undifferentiated human embryonic stem cell culture. Discovery of molecular and catalytic diversity among human diphosphoinositol-polyphosphate phosphohydrolases. Dynamic changes in fetal Leydig cell populations influence adult Leydig cell populations in mice. Lineage specification of ovarian theca cells requires multicellular interactions via oocyte and granulosa cells. Molecular mechanisms underlying female sex determination-antagonism between female and male pathway. Retinoic acid induces sertoli cell e paracrine signals for spermatogonia differentiation but cell autonomously drives spermatocyte meiosis. Steroidogenic factor 1 differentially regulates basal and inducible steroidogenic gene expression and steroid synthesis in human adrenocortical H295R cells. Licensing of primordial germ cells for gametogenesis depends on genital ridge signaling. Conditional ablation of Gata4 and Fog2 genes in mice reveals their distinct roles in mammalian sexual differentiation. Wt1 directs the lineage specification of sertoli and granulosa cells by repressing Sf1 expression. Sox9 expression during gonadal development implies a conserved role for the gene in testis differentiation in mammals and birds. Nuclear receptor steroidogenic factor 1 regulates the m llerian inhibiting substance gene: a link to the sex determination cascade. Fgf9 and Wnt4 act as antagonistic signals to regulate mammalian sex determination. Wnt signaling in ovarian development inhibits Sf1 activation of Sox9 via the Tesco enhancer. Role of homeobox genes in the patterning, specification, and differentiation of ectodermal appendages in mammals. Regulation of male sex determination: genital ridge formation and Sry activation in mice. Anomalies in human sex determination provide unique insights into the complex genetic interactions of early gonad development. Six1 and Six4 are essential for Gdnf expression in the metanephric mesenchyme and ureteric bud formation, while Six1 deficiency alone causes mesonephric-tubule defects. Six4, a putative myogenin gene regulator, is not essential for mouse embryonal development. Homeoproteins Six1 and Six4 regulate male sex determination and mouse gonadal development. Hoxa 11 structure, extensive antisense transcription, and function in male and female fertility. A conserved Hox axis in the mouse and human female reproductive system: Late establishment and persistent adult expression of the Hoxa cluster genes. Mechanisms of reduced fertility in Hoxa-10 mutant mice: uterine homeosis and loss of maternal Hoxa-10 expression. Genetic syndromes and genes involved in the development of the female reproductive tract: a possible role for gene therapy. Wnt-7a maintains appropriate uterine patterning during the development of the mouse female reproductive tract. It provides for the "gene shuffling" that leads to genetic diversity in populations, and also ensures the genomic integrity and correct number of chromosomes that produce healthy offspring. Meiosis is an area of intense investigation in the fields of developmental and reproductive medicine. Given the space limitations of this chapter, readers are frequently referred to many excellent reviews rather than primary literature. The goal of this chapter is to provide genetic perspectives on meiosis that are useful in the context of human health, fertility, and disease. The emphasis is on how the complex chromosomal dynamics of meiosis are revealed through the lens of insights derived from the analysis of mutations in the controlling genes. The purview extends beyond human biology to studies of meiosis in model animal organisms (particularly the laboratory mouse), which have identified many of the genes and proteins mentioned in this review (Table 3. Finally, human health concerns relevant to meiotic processes are discussed with the perspective that knowledge of meiotic mechanisms will enhance the understanding of human fertility, infertility, health, and disease. Additionally, mitosis yields genetically identical cells whereas meiosis produces genetically distinct cells that become the gametes. These defining features of meiosis are enabled by pairing and recombination between homologous chromosomes, which sets the stage for the two meiotic divisions. The end products form the haploid gametes, with one copy of each homologous chromosome. As the homolog pairing and synapsis processes progress, molecular recombination occurs between nonsister chromatids, a process beginning during the leptotene substage and lasting through the pachytene substage. After nuclear envelope breakdown, microtubules attach to kinetochores in metaphase I, followed by separation of homologs during anaphase I and cytokinesis in telophase at the end of the first meiotic division. In the ensuing second meiotic division, sister chromatids align at metaphase and segregate during anaphase and telophase, producing haploid germ cells (1N, 1C). There is considerable sexual dimorphism in the timing of meiotic events in mammals. In females (left panel), meiotic prophase is initiated during fetal development and then is arrested at the end of the first meiotic prophase, around the time of birth in mice. After ovulation and fertilization of the oocyte, meiosis is completed, resulting in a haploid female pronucleus. In males (right panel), from puberty onward continuous waves of germ cells enter meiosis. There is no arrest of meiosis in males, and it is completed over the course of a few weeks. Following the second meiotic division, haploid germ cells undergo extensive differentiation to form spermatozoa. Many of the key events of meiosis occur during the first lengthy meiotic prophase in five distinct substages, diagrammatically illustrated here. By diakinesis, the chromosome bivalents have fully condensed and the nuclear envelope breaks down, marking metaphase when the spindle microtubules attach to nonsister kinetochores, aligning the homologous pairs on the spindle, poised for separation. This is because the chiasmata holds the homologous chromosomes poised for segregation from each other at the onset of the first meiotic division. This, after the disassembly of chiasmata, allows the homologs to be pulled to opposite ends of the spindle at anaphase. Oocytes enter the first meiotic prophase embryonically and become arrested at the end of prophase in an extended diplotene configuration known as the dictyate stage. Massive numbers of oocytes undergo atresia at this point (and later during the ovarian cycles), a phenomenon that is not found in males. The dictyate stage in surviving oocytes can last for weeks and months (in the laboratory mouse) or decades (in humans). In addition to sexual dimorphism in the timing of meiotic events, the products of meiosis differ between males and females. In human females, gametogenesis ceases after roughly 50 years of age, but in males, sperm production can continue well into old age. Other aspects of sexual dimorphism in meiosis will be noted throughout this chapter. Gonadal Context of Meiosis Mammalian germ cells undergo meiosis only in the context of the gonad-the testis or the ovary-where they are in intimate contact with surrounding somatic cells, facilitating bidirectional signaling regulating the tempo of meiosis (The requirement for gonadal signaling is one reason underlying the difficulties in recapitulating germ-cell development ex vivo [87]). There are many excellent reviews on the contact and communication between germ cells and their surrounding somatic cells that are essential for their development [88­95]. It is not only the somatic cells immediately surrounding the germ cells that are crucial for meiosis, but also more distant cells are important because they are responsible for producing gonadal hormones essential for normal meiosis. The theca and Leydig cells, in the ovary and the testis, respectively, are the primary gonadal hormoneproducing cells. Theca cells comprise the outer layer of developing follicles, where they produce and transfer androstenedione to the granulosa cells for conversion by aromatase to 17-estradiol [96]. In the testis, the primary gonadal hormone produced by Leydig cells is testosterone, which is transported throughout the body. In the testis, germ cells develop in seminiferous tubules, where they are intimately associated with Sertoli cells, any one of which supports multiple germ cells at different developmental stages. Communication between Sertoli cells and germ cells is important for meiosis and development.

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