35 Sex Determination & Devlpt

35 Sex Determination & Devlpt - PSL302: Lecture 35,...

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Unformatted text preview: PSL302: Lecture 35, by French! Wednesday, Dec. 8, 2010 Sex Determination and Development Lecture Outline - Is the father or mother responsible for the sex of the child? - What is so special about the Y chromosome? - In all cases, does XY = boy and XX = girl? - How is puberty regulated? - How can reproduction stimulate neurogenesis? Suggested textbook reading: 829-834 (5E) 1. Is the father or mother responsible for the sex of the child? The FATHER - Recall: Somatic cells contain 46 chromosomes (diploid) - 22 matched pairs of autosomes - 2 sex chromosomes (Y = boy) - Meiosis reduces # chromosomes = 23 chromosomes in haploid gametes Answer: The father At 6 wks: bipotential stage At 6 weeks: the fetus has a bipotential - The fetus has a bipotential primordium & rudimentary m + and rudimentary male and female primordium fem reproductive tracts reproductive tracts - Bipotential primordium present ! = gonads are undiffated Y chromosome Female - Both male & female internal reproductive Male Bipotential ovary testis primordium tracts are present - Mullerian duct = f tract (in blue) What is so special about the Y chromosome? - Wolffian duct = m tract (in yellow Mllerian duct Wolffian duct - One will preferentially SRY gene that promotes testes development devlp in males & other Has will preferentially devlp in females epididymis Fallopian tube vas deferens uterus Usual development - Presence of Y chromosome male seminal vesicle upper vagina testis = devlpt of Wolffian duct - Absence of Y chromosome female Figure 26.3 ovary = devlpt of Mullerian duct 2. What is so special about the Y chromosome? - It has SRY gene = promotes testes devlpt Y chromosome? What is so special about the - If SRY gene is deleted: fetus devlps female phenotype but male genotype! Figure 26-2 Has SRY gene that promotes testes development SRY Usual development deletion - The SRY gene codes for gene regulatory protein (transcription factor) SRY - Act to alter transcription of several genes deletion 1 of 9 PSL302: Lecture 35, by French! Wednesday, Dec. 8, 2010 Function of SRY - SRY gene on Y chromosome expresses gene transcription factor SRY - SRY t.f. activates & regulates gene expression at SOX9 gene (on autosomal chromosome) - SOX9 gene also present in females, but not activated by SRY t.f. - SOX9 protein is master gene regulator - SOX9 t.f. activates transcription of many genes ! = Devlpt of Sertoli cells & formation of testes ! = Expression of anti-Mullerian hormone by ! Sertoli cells - SOX9 protein enhances expression of SOX9 gene ! = +ve feedback - Over time, SOX9 gene inhibits expression of SRY gene SOX9 protein initiates Sertoli cell differentiation - Early on in male gonads: activity of SOX9 causes expression of (fibroblast) growth factor - Occurs in bipotential primordium, which gives rise to gonads & testes ! = proliferation & diffation of Sertoli ! precursors Sertoli cells - Sertoli cells migrate to gonads' interior - Migrate & organize to form rudimentary seminiferous tubules, where spermatogenesis occurs ! = Form clusters around devlping germ cells - Later, another growth factor expressed ! = caused diffation of other gonad cells - Devlpt of testes: proliferation, diffation & migration of Sertoli cells, organization of tubules, vascularization; lastly, Leydig cell diffation Function of SRY SRY gene SRY +SOX9 gene SOX9 Transcription of many genes Development of Sertoli cells and testes Expression Sertoli cell differentiation SOX9 initiatesof Anti-Mllerian Hormone Proliferation of Sertoli precursors Sertoli precursors organize around clusters of germ cells Growth factor Growth factor Sertoli Precursor germ cell Fig. from Brennan J and Capel B (2004) Nature Reviews Genetics 5:509 Cellular events downstream of SOX9 rapidly organize testis structure i t ti t t XY XX proliferation bipotential gonad SRY Sertoli cell differentiation migration organization vascularization Leydig cell y g differentiation Diagram: Effect of SRY on sex determination Fig. from Brennan J and Capel B (2004) Nature Reviews Genetics 5:509 - Females w/o SRY lack lots of SOX9 expression ! = diff devlptal pattern - SOX9 promotes devlpt of testes: critical diffces caused by 2 hormones made by testes - Sertoli cells release anti-Mullerian hormone - Leydig cells release testosterone Cellular events downstream of SOX9 rapidly organize testis structure - SOX9 = devlpt of testes -> release of two hormones - Sertoli cells secrete anti-Mullerian hormones (destroys female-like structures) - Leydig cells secrete testosterone - Testosterone converted by 5-reductase DHT (dihydrotestosterone) 2 of 9 PSL302: Lecture 35, by French! Wednesday, Dec. 8, 2010 Hormones regulate sex differentiation -Y chromosome = SRY gene expressed -SRY t.f. activates SOX9 gene <-- SOX9 protein = devlpt of testes 2 types of cells DHT 2 hormones Preferential devlpt of m rudimentary int reproductive tract - Testosterone converts into DHT = devlptmale organs genitalia Development of internal of external male Devlpt of intermal male organs (bipotential stage of 6 wks) Figure 26-4 1) 6 wks: Bipotential primordium + male (W) & female (M) reproductive tracts present Figure 26-3a (a) Y chr, SRY gene SRY protein = SOX9 gene SOX9 protein (b) Devlpt of bipotential primordium into testes (c) Sertoli & Leydig cells = pdc of anti-Mullerian hormone + testosterone 2) 10 wks: Anti-Mullerian hormone = regression of Mullerian duct 3) Testosterone = devlpt of Wolffian duct internal male reproductive structures (a) DHT's only internal effect = prostate devlpt 3 of 9 PSL302: Lecture 35, by French! Wednesday, Dec. 8, 2010 Development of external male genetalia Devlpt of external male genitalia (after bipotential stage, ~10 wks) 1) Bipotential stage: devlpt of internal male reproductive structures Figure 26-3b (a) Genital tubercle, urethral groove & fold present 2) Presence of DHT at 10 wks: formation of ext male genitalia (a) Labioscrotal swelling: devlp into scrotum (b) Penis devlpt begins 3) At birth: testes descend from abdomen into scrotum Roles of testosterone and DHT Roles of testosterone and DHT (in adults) -Traditionally thought that this was all there was to sex determination -"Females are the default if SRY gene is absent" -But not quite as simple... -Genes needed for proper female devlpt Testosterone = red Dihydrotestosterone = blue What about females? Fig. from http://www.embryology.ch/anglais/ugenital/molec05.html What about females? - Genes involved in proper female devlpt: RSPO1, WNT4, -Cat - Many are gene regulatory proteins - In females: -catenin is a gene regulatory protein that suppresses SOX9 expression Genes including AMH - Expressed in males & females - SOX9 gene present in males & females - In females: any leaky expression is immediately shut off by -catenin -catenin is a gene regulatory protein that - BUT in males: if SOX9 highly expressed, inhibits -catenin = battle of the sexes! suppresses SOX9 expression. NO Anti-Mullerian Hormone nor testosterone - Suppression of SOX9 = NO anti-Mullerian hormone (AMH) nor testosterone 4 of 9 PSL302: Lecture 35, by French! Wednesday, Dec. 8, 2010 Top row: normal devlpt - In XY: SRY present - Expression of SOX9 - Testis organogenesis - Suppression of RSPO1/ WNT4/FOXL2/-catenin - In XX: SRY absent - RSPOetc. suppress SOX9 - Ovary organogenesis Bottom row: abnormal devlpt - In XY: SRY absent - RSPOetc. suppress SOX9 - Ovary organogenesis in genetic male - In XX: SRY absent - WNT4/FOXL2 absent - Leaky expression of SOX9 - Testis organogenesis in From Chia-Feng Liu CF et al , (2010) Current Topics in Developmental Biology 90:263 genetic female "Default": absent male (SRY) & female (RSPO1/WNT4/FOXL2) transcription factors - SOX9 expression gradually until testes are formed - So default is actually "male"! Devlpt of female internal organs (at 10 weeks) Development of female internal organs 1) 6 wks: Absence of SRY & genes inhibiting SOX9 Figure 26-3a primordium = ovary bipotential 2) 10 wls: Absence of testosterone = Wolffian duct degenerates (a) Absence of AMH = Mullerian duct devlpts into internal female reproductive structures 3) At birth: fallopian tube, uterus, upper part of vagina present 5 of 9 PSL302: Lecture 35, by French! Wednesday, Dec. 8, 2010 Development of female Devlpt of female external genitalia external genitalia 1) At 6 wks: bipotential stage = ext genitalia are identical to male at this stage Figure 26-3b (1 of 2) (a) Labioscrotal swelling = devlpt into labia 2) At 10 wks: in absence of androgens (no DHT), ext genitalia are feminized (a) Presence of clitoris 3) At birth: clitoris, labia majora & minora, & vaginal opening present 3. In all cases, does XY = boy and XX = girl? NO! Variations in sex determination & devlpt: atypical hormone lvls/action - XY: atypical androgen synthesis (e.g. [5-reductase] ) or action (receptors absent/nonresponsive) - XX: excessive exposure to androgens during early gestation (i.e. congenital adrenal hyperplasia) 1. Predict development in XY individual with complete (1) Predict devlpt in XY individual w/ complete androgen insensitivityy(receptors not fxnal). not functional) androgen insensitivity (androgen receptors g ( g p ) - Testes form but don't devlp - Sertoli & Leydig cells present - Testosterone & AMH secreted - But no hormone action! - No effects (green boxes absent) - Mullerian ducts don't regress - Testes don't devlp - DHT secreted BUT no ext genitalia Internal male genitalia? organs? testes Internal male organs? NO: testosterone can't act on Wolffian ducts - Testes remain undeveloped in abdomen External male External male genitalia? Phenotype? Phenotype? NO: AMH can't act to regress Mullerian ducts Female BUT not fertile - Has testis, not ovaries FYI - Lacks internal female http://www.thestar.com/living/health/article/801366--the-secret-sex reproductive structures 6 of 9 PSL302: Lecture 35, by French! Wednesday, Dec. 8, 2010 (2) Predict devlpt in XY individual w/ 5-reductase deficiency. defficiency y -Testes devlp but do not exit abdomen - Leydig & Sertoli cells secrete testosterone & AMH - Internal reproductive structures devlp - Mullerian duct regresses - Wolffian duct devlps - But external genitalia don't devlp - Also prostate doesn't devlp - Depends in amt of deficiency 2. Predict development in XY individual with 5- reductase testes Internal male organs? YES: testosterone secreted & acts on Wolffian duct - Devlpt of internal m structures (i.e. Testes) Internal I t l l External male genitalia? male organs? External male E t Phenotype? Ph l l Phenotype? t ? genitalia? NO: possibly female at birth - No DHT = no ext m genitalia - Some ambiguity re: ext structures Female at birth - But at puberty, genitalia may become more responsive to testosterone 3. Predict development in XX individual exposed to high levels (3) Predict devlpt in XX individual exposed to during fetalandrogens during fetal devlpt. of androgens high levels of development g g p - Have ovaries, not testes - No Sertoli/Leydig cells - No secretion of testosterone/AMH - Mullerian duct present - But external source of androgens - Possibly not sufficient to devlp Wolffian duct - Female genitalia deformed & masculinized - I.e. Clitoris looks like penis Internal male organs? NO: source not likely to be sufficient to devlp testes ovary Mllerian duct present External male male Internal genitalia? E t I t l l External male Phenotype? t l l Phenotype? Ph ? Ambiguous: female genitalia may be deformed organs? genitalia? Ambiguous Metamorphosis of the child into the adult Metamorphosis of child -> adult 3 Puberty = activation of the HPG axis resulting in gonad maturation - Puberty: activation of HPG axis = gonad maturation 3 Adolescence = maturation of adult - Process of becoming fertile social and cognitive behaviours g - Adolescence: maturation of adult social & cognitive behaviours 3 Coupling of both through interactions the nervous system - Coupling of gonad maturation & behaviours thru interacs btwn between steroid hormones and nervous system gonadal & gonadal steroid hormones birth 20 years 7 of 9 PSL302: Lecture 35, by French! Puberty: rapid 2010 Wednesday, Dec. 8,growth and development with earlier, more obvious signs in girls ith li b i i i il Boys Girls Puberty - Rapid growth & devlpt w/ earlier, more obvious signs in girls grow menarche enarche spurt - In girls: growth - 9-13 yrs: growth spurt test t t spurt pen pubic hair, breasts - ~12 yrs: menarche (first menstruation) p Puberty: rapid growth and development with li b i i in i l i 6 10 6 10 14 2 - ~14 yrs: 2 sex characteristics devlp, i.e. pubic hair,ith earlier, more obvious signs14 girls20 breasts - In boys: starts later Time (years) y Boys Girls - 11-18 yrs: growth spurt (longer than in girls = larger size) How is puberty regulat - 9-17 yrs: 2 sex characteristics devlp, i.e. testes, penis, hair growth menarche enarche spurt 4. How is puberty regulated? At onset of puberty, GnRH system is activated - Start up GnRH neurons in hypothalamus: travel down portal vein to ant pituitary - Immature stage (childhood): GnRH pulses are infrequent - Mature stage (puberty adulthood): GnRH pulses more rapid - LH & FSH secretion in anterior pituitary - Travel to gonads = devlpt of testes/ovaries growth spurt pubic hair, breasts At6the 10 14 of puberty, 6the10 14 system is onset GnRH 20 20 activated Time (years) y How is puberty regulated? testes t t penis pubic hair Sisk and Foster (2004) Nat Neurosci 7:1040 - Activation is complex - Devlptally regulated, ! i.e. to a clock - Internal cues - External cues - Integrate info from gonads to regulate GnRH activity - Sex steroids feedback - Steroid-independent mechs, i.e. % fat on time of menarche for girls Activation is complex p Sisk and Foster (2004) Nat Neurosci 7:1040 8 of 9 How can reproduction stimulate neurogenesis? PSL302: Lecture 35, by French! Wednesday, Dec. 8, 2010 Recall: Blood-brain barrier lecture from Dr. Mackay 5. How can reproduction stimulate neurogenesis? Recall: blood-brain barrier lecture from Dr. MacKay - At CSF-interstitial fluid barrier: cell layer lining ventricles are stem cell-like - Subependymal layer contains multipotent neural stem cells = give rise to progenitor cell pool - Progenitor cells migrate to rest of brain - Diffate into all types of glial cells or neurons - Specific brain regions to which progenitor cells migrate are: - Olfactory epithelium (smell) - Dentate gyrus (memory) - Neurogenesis happens in adults as well Dominant male mice trigger neurogenesis in females Expt: Dominant male mice trigger neurogenesis in females Specific regions to which p g p g progenitor cells migrate are: g olfactory epithelium (smell) and dentate gyrus (memory) - Among caged mice, 1 male dominates - Females capable of recognizing dominant male via pheromones b/c more attracted to them! - Pheromones act on olfactory epithelium-> bulb - Cause pituitary to secrete prolactin & LH - Signals brain to neurogenesis - New neurons make female more likely to mate with dominant male than w/ subordinate males - This happens w/ males & their own offspring - When they smell own offspring = neurogenesis - Able to recognize own offspring Evidence? Olfactory y epithelium Nasal cavity Olfactory bulb Dentate gyrus Pituitary Hypothalamus yp Fig. modified from DiRocco DP and Xia Z Nature Neuroscience 10:938-940 (2007) -Box d: control females, vs. Box e: females exposed to dominant male pheromones -Box e: more pink = more new neurons! Figures from: Mak GK et al (2007) al. Nature Neuroscience 10:1003-1011 1. Female exposed to dominant male pheromones for 7 days have more new neurons (pink) in dentate gyrus -If you inject LH/prolactin into brain region = more neurogenesis -If you use receptor knockouts, you lose neurogenesis -If this mech occurs in humans, huge potential market for perfumes & colognes! :-) 3. Using LH receptor knockout mice or PRL receptor knockout mice, showed LH receptors , p needed for new cells in dentate gyrus and PRL receptors needed for new cells in olfactory bulb 2. Injections of LH and PRL stimulate neurogenesis 9 of 9 ...
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