Developmental Biology 第七章性别决定及生殖发育 Sex determination and reproduction
Developmental Biology 第七章 性别决定及生殖发育 Sex determination and reproduction
Developmental Biology 、性别表现型的决定 公元前335年, Aristotle指出性别决定于热heat),当母亲子宫的 冷超过父亲的精热时子代发育为 Ifemale, female是发育不健全 的 men。 1600s/1700s,已认识到feme可以产生能够传递亲本性状的卵子。 19世纪末之前,人们认为温度、营养、年龄等环境因素决定了性 别。有利于能量和营养储存的因子将使一个人生产女婴,而 有利于能量和营养利用的因子则使人有男婴 20世纪初, Mendel定律重新发现(900、 Mcclung发现性染色体 (1902)、 Stevens和 Wilson在昆虫上发现了性染色体组成与性 别的关系(male= XYor Xo while female=XX(1905),从而认 识到遗传物质在性别决定中起重要作用
Developmental Biology 公元前335年，Aristotle指出性别决定于热(heat)，当母亲子宫的 冷超过父亲的精热时子代发育为female，female是发育不健全 的men。 1600s/1700s，已认识到female可以产生能够传递亲本性状的卵子。 19世纪末之前，人们认为温度、营养、年龄等环境因素决定了性 别。有利于能量和营养储存的因子将使一个人生产女婴，而 有利于能量和营养利用的因子则使人有男婴。 20世纪初，Mendel定律重新发现(1900)、McClung发现性染色体 (1902)、Stevens和Wilson在昆虫上发现了性染色体组成与性 别的关系(male=XY or XO while female=XX)(1905)，从而认 识到遗传物质在性别决定中起重要作用。 一、性别表现型的决定
Developmental Biology (一)、嘴乳动物的性别决定 1. Primary sex determination 指生殖腺发育为睾丸或卵巢的选择。胚胎生殖 腺( gonad)的发育命运决定于其染色体组成,Y染 色体的存在使生殖腺的体细胞发育为 testis而非 ovary。 eg,基因型为XXY的 Klinefelter综合症惠者的 表型为mae,但不具生殖力;基因型为XO的 Turner综合症患者为不能产卵的 female
Developmental Biology (一)、哺乳动物的性别决定 1. Primary sex determination: 指生殖腺发育为睾丸或卵巢的选择。胚胎生殖 腺(gonad)的发育命运决定于其染色体组成，Y染 色体的存在使生殖腺的体细胞发育为testis而非 ovary。 e.g., 基因型为XXY的Klinefelter综合症患者的 表型为male，但不具生殖力；基因型为XO的 Turner综合症患者为不能产卵的female
Developmental Biology INDIFFERENT CONADS (U o WEEKS 生殖嵴原基有两种发育方向: Testis-Ovary mesonephric wY cord ISTIS DEVELOTMENT OVARY DEVELOIMENT Wolffian danc Degenerating Cameral Differentiation of human gonads shown in transverse section. (A)Genital ridge df a tweek embryo. (B) Genital ndge ot a 6-week indifferent gonad showing primitive conls (O S wELKS sex cords (@) Testis development in the eighth week. The sex cords kee contact Tunica / Ath the Wolffian duct(E) Ovary drvelopment in an &week human四小 the Wolffian duct, and new cortical sex cmnd surround the germ cells that have Efferent uuds Granulosa cells differentiated from Cortical sex cords and thecal cells derived from wason durt mesenchymal cells form follicles (vas deferens Wa fan duct that envelop the germ cells (H 20 WCEKS
Developmental Biology 生殖嵴原基有两种发育方向： Testis－Ovary Granulosa cells differentiated from Cortical sex cords and thecal cells derived from mesenchymal cells form follicles that envelop the germ cells
(A) SEXUALLY INDIFFERENT Gonads Figure 20. 4 Summary of the development of gonads and their ducts in mammals. Note that both the Wolffian and Mullerian ducts Metanephric are present at the indiffcrent-gonad Me tage. The regional development of the Wolffian ducts depends on the mes- Ureter Wolffian enchyme that they encounter. Lower portions of the Wolffian duct that would MUllerian normally form the epididymis will form seminal vesicle tissue if cultured with mesenchyme associated with the upp (seminal vesicle) portions of the duct. (Higgins et al., 1989) Epididymis Metanephric Oviduct kidneys Ovaries Ureters Degenerated D Mullerian duct Urinary Urinary bladder Mullerian duct Wolffian duct (vas deferens) Uterus (B) MALE (C) FEMALE GONADS Gonadal type Testis Sex cords Medullary (internal Cortical (external) DUCTS Remaining duct Wolffian for germ Duct differentiation Vas deferens, epididymis, Oviduct, uterus, cervix, seminal vesicle upper portion of vagina
Developmental Biology
Developmental Biology 哺乳动物性特征的发育机制 Female intemal Follicular genitalia OVARY Follicles (uterus, oviduct DXT Theca cervix, upper vagina) ANTe Genital Bipotential Mullerian duct SKY LAX sox2 Sertoli sFT AMH lIs b Regression IESTIS -+ Testosterone Genital tubercle urogenital sinus Penis prostate Wolffia Male internal duct genitalia didymus, vas deferens seminal vesicle) Figure 20.2 Postulated cascades leading to the for- chromosome)in conjunction with auto- major hormones. The first, anti mation of the sexual phenotypes in somal genes such as SOX9. The ovary Mullerian duct factor(AMH), causes mammals. The conversion of the genital makes thecal cells and granulosa cells, the Muillerian duct to regress. The sec the sri and WTi genes, since mice lack- ing estrogen. Under estrogen (first from tion of the Wolffian duct into the map ridge into the bipotential gonad needs which together are capable of synthesiz- ond, testosterone, causes the differenti ing either of these genes lack gonads. the mother, then from the gonads), the internal genitalia. In the urogenital The bipotential gonad appears to be Mullerian duct differentiates into the region, testosterone is converted into moved into the female pathway by the female genitalia and the offspring dihydrotestosterone(DHT), and this Wnt4 or DAXI genes and into the male develop the secondary sex characteris- hormone causes the morphogenesis of pathway by the SkY gene(on the Y tics of females. The testis makes two the penis and prostate
Developmental Biology 哺乳动物性特征的发育机制 LHX9
Developmental Biology 睾丸决定基因为Y染色体上的SRY (sex-determining region of the Y chromosome Fig 12.2 Sex reversal in humans due requent Rare to chromosomal exchange At meiosis exchange exchange in male germ cells, the X and Y chromo somes pair up(center panel) and there X XY×Y is often crossing over of the distal region (blue cross), which does not affect sexual development (left panel). On rare occasions SRY IN SRY crossing over involves a larger segment that includes the SRY gene(red cross so that the x chromosome now carnes this male-determining gene (right panel). After Goodfellow. P.N. et al. 1993 SRY是通过分析XX的men和XY的 women的DNA而发现的(1990) 它是一种编码223a的转录因子,含有 HMG DNA结合区
Developmental Biology 睾丸决定基因为Y染色体上的SRY (sex-determining region of the Y chromosome) SRY是通过分析XX的men和XY的women的DNA而发现的(1990)。 它是一种编码223 aa的转录因子，含有HMG DNA结合区
Developmental Biology Sry对睾丸发育的影响的实验证据 小鼠Sry基因也存在于Y染色体上,在未分化的生殖腺和 正在分化为睾丸的生殖腺中表达。转Sry基因的XX小鼠 可长出睾丸和雄性特征,但不能产生正常的精子。 XX - Control (A) (B) XY XX Figure 20.6 XX mouse transgenic for Sry is male. (A)Polymerase chain reaction followed by electrophoresis shows the presence of the Sry gene in normal XY males and in a transgenic XX Sry mouse. The gene is absent in the female XX littermate. (B)The as in an XY male(left).(From Koopman et al., 1991, photograph courtesy of the external genitalia of the transgenic mouse are male(right) and essentially the san authors
Developmental Biology 小鼠Sry基因也存在于Y染色体上，在未分化的生殖腺和 正在分化为睾丸的生殖腺中表达。转Sry基因的XX小鼠 可长出睾丸和雄性特征，但不能产生正常的精子。 Sry对睾丸发育的影响的实验证据 XY XX
Develop sryf的直接作用模型:s直接诱导雄性生殖嵴特异性基因的表达 Sry的间接作用模型:sn诱导生殖嵴细胞合成某种因子→中肾细胞进入生 殖嵴→诱导生殖嵴表皮细胞转变为睾丸支柱细胞、并表达雄性特异性基因。 Figure 17.7 12-1y Migration of the mewonephr cells into Sn gonadal rudn C)(mmtm钟 nd gonadal rudiments) were collected from 12-day embronic mice. One of the ice was market with a B-galactosidas tran xX+ Sry XOr XY oN XY .lrv or XX) I he goat and meone bine, usint gonadal tissue from unlabeled mice and meo nephros from Labeled mice. (A) Migration of mesonephric RTme cells into the gonad was seen when the gonadal cell wet GAy XY or when they were XX with an Sry transgene (N) No Mesons was Men when the gonad contained cither xX cela or xXY cells in whih the Y chromosome had a deletion in theSr gene. The sex chromosomes of the mesonephros did not nAkd上地 tthe"s ducts and the developing gonad in the l6 lay ation, (C) Intimate relation between the uy cytokeratin-s, wD). Wolfun duct(A, B after Cape eta 1999. photographs courtesy of B, Capel C from Sariola and urma 199), photograph courtesy of H Sariola. coculture A Sry: Allows migration -Sryt No mesonephric cell migration
Developmental Biology Sry的直接作用模型：Sry直接诱导雄性生殖嵴特异性基因的表达。 Sry的间接作用模型：Sry诱导生殖嵴细胞合成某种因子→中肾细胞进入生 殖嵴→诱导生殖嵴表皮细胞转变为睾丸支柱细胞、并表达雄性特异性基因
Developmental Biology 与睾丸命运决定有关的常染色体基因 Sox9:为含 HMG DNA结合区的转录因子。含一个额外的 SOX9的 SHuman将发育为mae;而75%的、只含一个有功能的 SOX9的 HUmans发育为 Ifemale或两性人 小鼠的Sox9只在雄性生殖嵴中表达,表达时间比Sry约晚 S0x9蛋白可与Amh的启动子结合,促进Amh的表达。 SF( steroidogenic factor1):为含 HMG DNA结合区的转录 因子。S们在雌雄小鼠的未分化的性腺中都表达,但分化开始后就局 限在XY小鼠的正在发育的睾丸中。SF1在睾丸支柱细胞中通过协助 Sox9而增强AM基因的表达( see next slide);而在睾丸的间质细胞中, 它可激活睾丸酮合成酶基因
Developmental Biology 与睾丸命运决定有关的常染色体基因 Sox9：为含HMG DNA结合区的转录因子。含一个额外的 SOX9的XX human 将发育为male; 而75%的、只含一个有功能的 SOX9的XY humans发育为female或两性人。 小鼠的Sox9只在雄性生殖嵴中表达，表达时间比Sry约晚。 Sox9蛋白可与Amh的启动子结合，促进Amh的表达。 SF1(steroidogenic factor 1)：为含HMG DNA结合区的转录 因子。Sf1在雌雄小鼠的未分化的性腺中都表达，但分化开始后就局 限在XY小鼠的正在发育的睾丸中。SF1在睾丸支柱细胞中通过协助 Sox9而增强AMH基因的表达(see next slide);而在睾丸的间质细胞中， 它可激活睾丸酮合成酶基因