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Speaker: Chen, TuoHuan

總計 25 張投影片. ●. Speaker: Chen, TuoHuan. Laboratory of Animal Proteomics, Department of Animal Science, National Chung Hsing University, Republic of China (Taiwan). 生殖生物學特論 期末報告. Review. TRENDS Endocrinol Metab. 16: 19-25 (2005). Signaling at the Crossroads of Gonad Development.

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Speaker: Chen, TuoHuan

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  1. 總計 25 張投影片 ● Speaker:Chen, TuoHuan Laboratory of Animal Proteomics, Department of Animal Science, National Chung Hsing University, Republic of China (Taiwan) 生殖生物學特論 期末報告 Review TRENDS Endocrinol Metab. 16: 19-25 (2005) Signaling at the Crossroads of Gonad Development Andrea J. Ross and Blanche Capel Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, USA.

  2. Outline Gonadal RidgeWhere is the gonadal ridge? How does the gonadal ridge look like? Mammalian Gonad DevelopmentY-Linked Sex-specific gonad development PGC first detected … 7.2 Sry (sex-determining region of chromosome Y) … 10.5-12.0 Sertoli cells differentiated in XY gonad … 11.2-12.5 Leydig cells differentiation … 12.5-13.5 Pathways that repress testis development in XX gonads Testicular designation in Poultry The ZZ and ZW sex determination days post coitum

  3. Introduction Gonad is bipotential. 性腺具有雙重發育潛能。 • The gonad is the organ that makes gametes. The gonads in males are the testes and the gonads in females are the ovaries • During organogenesis, the processes of cell proliferation, differentiation, migration and death are precisely regulated by complex signaling networks.

  4. Developmental Biology of Gonads Differentiation of the mammalian gonads provides a particulary useful model with which to examine mechanisms of cell signaling during organ development. The gonadal anlage is unique among organ primordia in that it can follow one of two developmental paths: namely, it can differentiate as either a testis or an ovary. The bipotential nature of the gonad makes it an ideal system with which to study the mechanisms that direct cell fate decisions and also provides an opportunity to use comparative approaches that are not feasible in other systems. Recently, significant efforts has focused on identifying the signaling pathways that direct morphogenesis of the testis and overy. Several signaling molecules has been shown to have crucial (發生學) 元生細胞 始基細胞 /複數 器官發生/型態發生

  5. functions in gonad differentiation, including members of the fibroblast growth factor (FGF) , platelet derived growth factor (PDGF) , Wnt and transforming growth factor-β families. Some genes, which are in the species of mouse and human, were indicated as signaling molecules of which mutations will disrupt testis or ovary differentiation. 纖維母細胞生長因子 血小板源生長因子 一種訊號醣蛋白 轉化生長因子 Table 1. Mutations in signaling molecules that disrupt testis or ovary differentiation

  6. Murine Gonadogenesis 鼠科動物的性腺生成 • In the mouse, the gonad arises at about 10.0 days post cotium(dpc) as a thickening of the epithelium along the coelomic surface of the mesonephros . • Proliferation of these epithelial cells gives rise to somatic cells in the gonad. By contrast, the germ cell lineage arise outside the urogenital ridge before formation of the gonads. 交配後 中腎，胚胎過濾廢物的暫時性器官

  7. Mouse primordial germ cells are specified in the epiblast and are first detected at about 7.2 dpc in a region posterior to the primitive streak. PGCs proliferate and migrate through the gut mesentery into the urogential ridge and populated the gonads between 10.0 and 11.0 dpc. 外胚層 1 PGC 2 Allantois 3 Cloacal membrane 4 Epiblast 5 Pharyngeal membrane 6 Heart anlage 7 Umbilical vesicle (yolk sac) 8 Endoderm 9 Mesoderm 1 Rectum 2 Omphalomesenteric duct 3 Allantois 4 Nephrogenic cord (pink) 5 Gonadal ridge (green) 6 PGC 7 Heart anlage Figure 1. Migration of PGC.

  8. Sex-specific gonad development is initiated when Sry(Sex-determining region of chromosome Y) is expressed in the somatic cells of the XY gonad between 10.5 and 12.0 dpc. Sry encode a putative transcription factor that acts as the genetic switch for male development. Sry is required for testis formation in XY embryos and Sry is sufficient to induce testis differentiation in XX embryos. Shortly after the initiation of Sry expression, there is a marked increase in the proliferation of coelomic epithelial cells in XY gonads. Between 11.2 to 12.5 dpc, Sertoli cells differentiate in the XY gonad and organized into a testis-specific vasculature. The Leyding cells differentiate between 12.5 and 13.5 dpc in the interstitical space between cords.

  9. Figure 2. Early murine gonad differentiation. The bipotential gonad (yellow) initially forms as a thickening of the coelomic epithelium of themesonephros(gray). Between 9.5 and 11.5 dpc, primordial germ cells (green) migrate from the hindgut into the urogenital ridges and populate the gonads. Between 10.5 and 12.0 dpc, the Y-linked gene Sry is expressed specifically in the XY gonads, where it triggers the testis differentiation pathway. The earliest features of testis development include the differentiation of Sertoli cells (purple), which enclose germ cells to form testis cords, and the formation of a male-specific vasculature (red). These events are followed by the differentiation of steroidogenic Leydig cells (blue) in the testis interstitium, starting at about 12.5 dpc. By contrast, no marked morphological changes are observed in the XX gonads until 13.5 to 14.5 dpc, when germ cells enter the prophase of meiosis. 9.5 migrate 10.5 Sry expressed 12.5 Leydig Cells 11.2 Sertoli Cell

  10. Morphological Changes in XX Gonads By contract, few visible morphological changes occur in XX gonads during this time period. The first overt feature of ovarian development is eatery of the germ cells into the prophase of meiosis, which occurs in an anterior-to-posterior wave between 13.5 and 14.5 dpc. 13.5 Germ cell meiosis and other aspects of ovarian differentiation

  11. Sertoli cell Determination 賽托利細胞的決定與分化 • Sry, Sox9 and Fgf9 are three key genes. Sertoli cells show a strong bias for presence of the Y chromosome. Y-linked gene Sry is required only in the Sertoli cell lineage. Sox9 is thought to be a direct target of Sry on the basis of its early expression shortly after the onset of Sry expression. • There are also insulin and insulin like growth factor (IGF) family signaling involved.

  12. Brief Summary The gonad is bipotential. Bipotential Gonad Sry SOX9 Wnt4 ? ? Fgf9 Igf1 DAX1 DHH PDGF AMH Male Female

  13. Help Big Bird find the right room. Woops, which room should I go? ZW Gentlebird this way In the XY sex-determination system, females have two of the same kind of sex chromosome (XX), while males have two distinct sex chromosomes (XY). Some species (including humans) have a gene SRY on the Y chromosome that determines maleness; others (such as the fruit fly) use the presence of two X chromosomes to determine femaleness. The XY sex chromosomes are different in shape and size from each other unlike the autosomes, and are termed allosomes. ZZ The ZW sex-determination system is found in birds and some insects and other organisms. The ZW sex-determination system is reversed compared to the XY system: females have two different kinds of chromosomes (ZW), and males have two of the same kind of chromosomes (ZZ). In bird, the females is the heterogametic (ZW) sex, but W chromosomal genes do not influence gonadal development in a way similar to SRY gene on the mammalian Y chromosome. 雌禽是異配子 ZW，但 W 染色體對性別的影響與哺乳類 SRY 基因並不相同

  14. In birds the female is heterogametic (ZW) sex, but W chromosomal genes do not influence gonadal development in a way similar to the SRY gene on the mammalian Y chromosome. However, autosomal genes such as SRY-like HMG box gene 9 (SOX9) may influence gonadal development. In birds, hormonesaffect development. Male gonads subjected to estrogen form an ovotestis, whereas ovaries exposed to aromatase inhibitors from an atypical testis. Testicular Designation Hormone treatment 位置 哺乳動物 SRY gene Y 染色體 鳥類 SOX9 gene 常染色體

  15. Birds In birds however, females are the heterogametic sex, carrying one copy of each of the so called Z and W sex chromosomes, whereas males are homogametic ZZ. The Z and W chromosomes have no relation to the mammalian X and Y, and in fact seem to have evolved from different pairs of autosomes. And this is part of the reason we are not yet certain which of the two carries the genetic trigger for sex determination [38,39]. To this day, there are two major theories under investigation. Sex may depend on Z chromosome dosage, according to the example of Drosophila melanogaster and C.elegans. One candidate gene for this theory is the DMRT1, which is located on Z chromosomes, escapes dosage compensation and is expressed specifically in the gonads, and is thus capable of linking the number of Z chromosomes with gonadal differentiation [40,41]. 雄鳥與雌鳥分別是 ZZ/ZW，雌鳥是異配子型。而且鳥類的 Z 與 W 染色體和哺乳動物的 X 和 Y 染色體是無關聯的。也因此，我們還未能確定到底是哪個基因 trigger 性別決定。 其中一個理論是經由果蠅和線蟲研究而來的。註: 線蟲是雌雄同體。 Z 染色體上的 DMRT1 是在性腺特定表現的基因，由數量決定鳥類的性別。 According to one theory, the ZPKCI proteins form homodimers in ZZ males that stimulate a factor required for the differentiation of the testes. Whereas in ZW females, the ASW (also known as WPKCI) proteins form heterodimers with ZPKCI that may prevent the activation of that factor or stimulate directly the differentiation of ovaries. 鳥類 Z 染色體 DMRT1 假說: DMRT1基因的數量決定性別 Figure 3. The role of ZPKCI and ASW (WPKCI) in ZW sex determination. (Panagiota Manolakou et al., 2006)

  16. On the other hand, sex may be determined by the feminizing presence of the W chromosome, following the example of Y in eutherian mammals. There are two different mechanisms that are being studied and can support this theory. One includes the FET1 gene, which is located on W, does not have a Z homologue and is expressed almost exclusively in the female urogenital system [18]. The other includes the ASW gene, also known as WPKCI, and its Z homologue ZPKCI, since it has been proposed that the products of those two genes are capable of dimerisation, with a ZPKCI homodimer acting as a testis factor and a WPKCI/ZPKCI heterodimer preventing this effect (see Figure 14) [39-41]. One way to discern between the two theories would be to look into different combinations of Z and W chromosomes. Indeed, scientists have studied ZW aneuploidy in an effort to better understand how things work. It turns out that ZZZ animals develop testes but are infertile, ZWW animals die early in embryonic development, but ZZW combinations manifest as intersexual: the animals appear female on hatching, but slowly turn into males at sexual maturity. It is still possible, thus, that a combination of the above is in fact applied [40,42]. 另一個理論是性別由 W 染色體決定。這個理論是，其中 W 染色體的基因有 FET1 基因，這個基因是 Z 染色體沒有的，而在雌禽尿道生成系統中特有表現。 兩條染色體都有 ASW基因，W 染色體的又稱為WPKCI基因，Z 染色體的稱為 ZPKCI 基因，這兩個基因的產物會結合在一起。而因此，Z 染色體的同源 ZPKCI 是作為促進生成睪丸因子；相反的， WPKCI/ZPKCI 體則無法促使睪丸生成。 用來檢視上述 2 個理論的方法之一是利用非整倍體。ZZZ 動物會發育出睪丸，但卻無生育力；ZZW 組合則會造成中間性別，孵化的時候是雌性的，但當接近性成熟的時候，會緩慢的轉變為雄性。 鳥類 分別位於 Z, W染色體 WPKCI 假說: WPKCI ZPKCI 結合導致誘導睪丸生成的 ZPKCI 失去作用 ZPKCI (Panagiota Manolakou et al., 2006)

  17. Mammals are default females, requiring switching by a gene known as SRY located on the Y chromosome. Expression of this gene causes conversion of undifferentiated gonadal tissue into a testis. The SRY gene code for a DNA-binding high mobility group (HMG) box protein that help promote genes “downstream” that influence sexual development. That is, gene expression often requires numerous transcriptional regulators. The gene SRY is member of a family of genes known as SRY-like HMG box genes (SOX genes), and the SOX genes are highly conserved in vertebarte animals. However, there is no homologus of the “SRY genes” in Aves. 脊椎動物 哺乳動物 SOX genes SRY gene 鳥類 其他脊椎動物，則有　相似的基因，稱為 SOX基因，具有高度保留性 SRY gene (Thurston and Korn, 2000)

  18. 哺乳動物 SRY gene 鳥類 SOX9 gene 鳥類 DMRT1 性別分化時，各基因相對表現量。(a) 小鼠 (b) 雞虛線表示低表現量，細線表示中度表現量，粗線表示高表現量。 Figure 4. Relative gene expression in male and female gonads during the period of sex determination of embryogenesis in (a) mouse, (b) chicken. Dotted lines indicate low expression; thin lines indicate moderate expression and thick lines indicate strong expression. The relative levels of expression for a given gene are comparable between the sexes of a given species and not between species or between genes in the same species. SRY: sex-determining region on the Y chromosome; SOX9: Sry-like HMG box; AMH: anti-Müllerian hormone; WT1: Wilms’ tumour suppressor gene; SF1: steroidogenic factor 1; DAX1: dosage sensitive sex-reversal-adrenal hypoplasia congenita-critical region of the X chromosome, gene 1; DMRT1: doublesex- and mab-3-related transcription factor 1; dpc: days post coitus; TC: testis cord. (Morrish and Sinclair, 2002)

  19. Recently, it was reported that genes containing a novel DNA-binding domain (DMRT1) are expressed in the genital ridge and Wolffian duct tissue prior to sexual differentiation. Although the exact role that the various genes play in avian sex differentiation is uncertain, it appears that there is a fundamental rolefor SOX9 in testis formation. The uncertainty lies in the timing of expression of these genes relative to testicular development. A important regulating protein for maleness is anti-Müllerian hormone (AMH). This hormone, produced by Sertoli cells, inhibits formation of the female ductal system from Müllerian tissue, may inhibit aromatase activity and is thought to be involved in testicular differentiation and morphogenesis. 哺乳動物 AMH 苗勒氏抑制素是由賽透力氏細胞分泌，會抑制芳香環轉化酶活性，同時與睪丸分化與形態有關 鳥類 AMH

  20. Sertoli cell numbers are set early in spermiogenesis, possibly under the influnece of follicle-stimulating hormone and thyroid hormone. Setroli cells make a number of substance that affect testicular development and function particularly anti-Müllerian hormone, which inhibits female oviduct formation from the Mullerian anlage, inhibits aromatase activity to stop estrogen production. However, others reported that chicken AMH appears before SOX9 expression.

  21. Conclusion Understanding of the signaling events that regulate testis and ovary has greatly increased in recent years. How Sry tips the balance towards Sertoli cell differentiation in the XY gonad, however, remains unclear. Downstream of this event, numerous signaling molecules including FGF9, DHH and PDGF promote Sertoli differentiation and recruit other cells in the XY gonad to the testis pathway. But direct molecular links between SRY and these signaling pathway have not been established. Sex determination in mammals requires the presence of Sry gene, however, poultry is lack of this gene. The sex determination in poultry might be either WPKCI/ZPKCI theory or by different level of DMRT1.

  22. This photo of an opened oviduct with an ectopic pregnancy features a spectacularly well preserved 10-millimeter embryo. It is uncommon to see any embryo at all in an ectopic, and for one to be this well preserved (and undisturbed by the prosector's knife) is quite unusual.Even an embryo this tiny shows very distinct anatomic features, including tail, limb buds, heart (which actually protrudes from the chest), eye cups, cornea/lens, brain, and prominent segmentation into somites. The gestational sac is surrounded by a myriad of chorionic villi resembling elongate party balloons. This embryo is about five weeksold (or seven weeks in the biologically misleading but eminently practical dating system used in obstetrics).The photo was taken on Kodak Elite 200 slide film, with a Minolta X-370 camera and 100mm f/4 Rokkor bellows lens at near-full extension. The formalin-fixed specimen was immersed in tapwater and pinned to a tray lined with black velvet. The exposure was 1/4 second at f/8.Photograph by Ed Uthman, MD. Placed in the public domain and originally posted to the Web on 12 Oct 2001

  23. CLOVERICA ACIREVOLC Thanks For Your Attention and Any Comments?

  24. Introduction Gonadal Anlage is UniqueThe gonadal anlage is unique among organ primordria in that it can follow one of two developmental paths: namely, it can differentiated as either a testis or an ovary. Bipotential Nature of the GonadThe bipotential nature of the gonad make it an ideal system with which to study the mechanism that direct cell fate decision and also provides an opportunity to use comparative approaches that are not feasible in other systems. Identifying the Signaling PathwayRecently, effort has focused in identifying the signaling pathways that direct morphogenesis of the testis and ovary.

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