Role of mammalian Y chromosome in sex determination

It has long been assumed that the mammalian Y chromosome either encodes, or controls the production of, a diffusible testis-determining molecule, exposure of the embryonic gonad to this molecule being all that is required to divert it along the testicular pathway. My recent finding that Sertoli cells in XX ↔ XY chimeric mouse testes are exclusively XY has led me to propose a new model in which the Y acts cell-autonomously to bring about Sertoli-cell differentiation. I have suggested that all other aspects of foetal testicular development are triggered by the Sertoli cells without further Y-chromosome involvement. This model thus equates mammalian sex determination with Sertoli-cell determination. Examples of natural and experimentally induced sex reversal are discussed in the context of this model.

Download Full-text

Inheritance of T-associated sex reversal in mice

Genetics Research ◽

10.1017/s001667230003528x ◽

1990 ◽

Vol 56 (2-3) ◽

pp. 185-191 ◽

Cited By ~ 19

Author(s):

Linda L. Washburn ◽

Barbara K. Lee ◽

Eva M. Eicher

Keyword(s):

Sex Determination ◽

Inbred Strain ◽

Y Chromosome ◽

Ovarian Tissue ◽

Testicular Tissue ◽

Gonadal Development ◽

Sex Reversal ◽

Testicular Development ◽

Additional Locus ◽

Strain Background

SummaryWe previously identified a primary sex-determining locus,Tas, on mouse Chr 17 that causes ovarian tissue development in C57BL/6JThp/ + andTorl/ + individuals if the AKR/J Y chromosome is present. We hypothesized thatTasis located within the region of Chr 17 deleted byThpandTorland that C57BL/6J carries a diagnosticTasallele, based on the observation that ovarian tissue develops in XY mice whenThpis on a C57BL/6J inbred strain background, whereas normal testicular development occurs whenThpis on a C3H/HeSnJ inbred strain background. To test this hypothesis, we mated (C57BL/6J × C3H/HeSnJ)F1 females to C57BL/6JThp/ + hermaphrodites. As expected, half of the XYThp/+ offspring developed ovarian and testicular tissue while half developed exclusively testicular tissue. Unexpectedly, the inheritance of selected Chr 17 molecular loci was independent of gonadal development, as half of the male and hermaphroditic offspring inherited C3H/HeSnJ-derived Chr 17 loci and half inherited C57BL/6J-derived Chr 17 loci. We conclude that for ovarian tissue to develop in an XYThp/ + or XYTort/ + individual (1)Tasmust be present in a hemizygous state, which is accomplished by heterozygosity for theThporTortdeletions; (2) the AKR/J-derived Y chromosome must be present; and (3) an additional locus involved in primary sex determination must be present in a homozygous C57BL/6J state. This newly identified gene may be one of the previously defined loci,tda-1ortda-2.

Download Full-text

Roles of Anti-Müllerian hormone (Amh) and its duplicates in sex determination and germ cell proliferation of Nile tilapia

Genetics ◽

10.1093/genetics/iyab237 ◽

2021 ◽

Author(s):

Xingyong Liu ◽

Shengfei Dai ◽

Jiahong Wu ◽

Xueyan Wei ◽

Xin Zhou ◽

...

Keyword(s):

Cell Proliferation ◽

Sex Determination ◽

Germ Cell ◽

Y Chromosome ◽

X Chromosome ◽

Nile Tilapia ◽

Critical Period ◽

Sex Reversal ◽

Homozygous Mutation ◽

Germ Cell Proliferation

Abstract Duplicates of amh are crucial for fish sex determination and differentiation. In Nile tilapia, unlike in other teleosts, amh is located on X chromosome. The Y chromosome amh (amh△-y) is mutated with 5 bp insertion and 233 bp deletion in the coding sequence, and tandem duplicate of amh on Y chromosome (amhy) has been identified as the sex determiner. However, the expression of amh, amh△-y and amhy, their roles in germ cell proliferation and the molecular mechanism of how amhy determines sex is still unclear. In this study, expression and functions of each duplicate were analyzed. Sex reversal occurred only when amhy was mutated as revealed by single, double and triple mutation of the three duplicates in XY fish. Homozygous mutation of amhy in YY fish also resulted in sex reversal. Earlier and higher expression of amhy/Amhy was observed in XY gonads compared with amh/Amh during sex determination. Amhy could inhibit the transcription of cyp19a1a through Amhr2/Smads signaling. Loss of cyp19a1a rescued the sex reversal phenotype in XY fish with amhy mutation. Interestingly, mutation of both amh and amhy in XY fish or homozygous mutation of amhy in YY fish resulted in infertile females with significantly increased germ cell proliferation. Taken together, these results indicated that up-regulation of amhy during the critical period of sex determination makes it the sex-determining gene, and it functions through repressing cyp19a1a expression via Amhr2/Smads signaling pathway. Amh retained its function in controlling germ cell proliferation as reported in other teleosts, while amh△-y was nonfunctionalized.

Download Full-text

CX43 expression, phosphorylation, and distribution in the normal and autoimmune orchitic testis with a look at gap junctions joining germ cell to germ cell

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00500.2010 ◽

2011 ◽

Vol 300 (1) ◽

pp. R121-R139 ◽

Cited By ~ 13

Author(s):

R.-Marc Pelletier ◽

Casimir D. Akpovi ◽

Li Chen ◽

Robert Day ◽

María L. Vitale

Keyword(s):

Cell Differentiation ◽

Gap Junctions ◽

Germ Cell ◽

Sertoli Cell ◽

Sertoli Cells ◽

Seminiferous Tubule ◽

Connexin 43 ◽

Cx43 Expression ◽

Cx43 Protein ◽

Cx43 Mrna

Spermatogenesis requires connexin 43 (Cx43).This study examines normal gene transcription, translation, and phosphorylation of Cx43 to define its role on germ cell growth and Sertoli cell's differentiation, and identifies abnormalities arising from spontaneous autoimmune orchitis (AIO) in mink, a seasonal breeder and a natural model for autoimmunity. Northern blot analysis detected 2.8- and a 3.7-kb Cx43 mRNA bands in seminiferous tubule-enriched fractions. Cx43 mRNA increased in seminiferous tubule-enriched fractions throughout development and then seasonally with the completion of spermatogenesis. Cx43 protein levels increased transiently during the colonization of the tubules by the early-stage spermatocytes. Cx43 phosphorylated (PCx43) and nonphosphorylated (NPCx43) in Ser368 decreased during the periods of completion of meiosis and Sertoli cell differentiation, while Cx43 mRNA remained elevated throughout. PCx43 labeled chiefly the plasma membrane except by stage VII when vesicles were also labeled in Sertoli cells. Vesicles and lysosomes in Sertoli cells and the Golgi apparatus in the round spermatids were NPCx43 positive. A decrease in Cx43 gene expression was matched by a Cx43 protein increase in the early, not the late, phase of AIO. Total Cx43 and PCx43 decreased with the advance of orchitis. The study makes a novel finding of gap junctions connecting germ cells. The data indicate that Cx43 protein expression and phosphorylation in Ser368 are stage-specific events that may locally influence the acquisition of meiotic competence and the Sertoli cell differentiation in normal testis. AIO modifies Cx43 levels, suggesting changes in Cx43-mediated intercommunication and spermatogenic activity in response to cytokines imbalances in Sertoli cells.

Download Full-text

Role of autonomous and non-autonomous sex determination signals in sexually dimorphic development of the Drosophila embryonic gonad

Developmental Biology ◽

10.1016/j.ydbio.2007.03.114 ◽

2007 ◽

Vol 306 (1) ◽

pp. 313 ◽

Cited By ~ 2

Author(s):

N.R. Crnkovich ◽

T.J. DeFalco ◽

S Le Bras ◽

A.L. Casper ◽

M.B. Van Doren

Keyword(s):

Sex Determination ◽

Sexually Dimorphic ◽

Embryonic Gonad

Download Full-text

Exogenous Gonadotrophin Stimulation Induces Partial Maturation of Human Sertoli Cells in a Testicular Xenotransplantation Model for Fertility Preservation

Journal of Clinical Medicine ◽

10.3390/jcm9010266 ◽

2020 ◽

Vol 9 (1) ◽

pp. 266 ◽

Cited By ~ 2

Author(s):

Marsida Hutka ◽

Lee B. Smith ◽

Ellen Goossens ◽

W. Hamish B. Wallace ◽

Jan-Bernd Stukenborg ◽

...

Keyword(s):

Sertoli Cell ◽

Sertoli Cells ◽

Connexin 43 ◽

Xenograft Model ◽

Cell Maturation ◽

Human Testis ◽

Testicular Development ◽

Future Fertility ◽

And Function ◽

Testis Tissue

The future fertility of prepubertal boys with cancer may be irreversibly compromised by chemotherapy and/or radiotherapy. Successful spermatogenesis has not been achieved following the xenotransplantation of prepubertal human testis tissue, which is likely due to the failure of somatic cell maturation and function. We used a validated xenograft model to identify the factors required for Leydig and Sertoli cell development and function in immature human testis. Importantly, we compared the maturation status of Sertoli cells in xenografts with that of human testis tissues (n = 9, 1 year-adult). Human fetal testis (n = 6; 14–21 gestational weeks) tissue, which models many aspects of prepubertal testicular development, was transplanted subcutaneously into castrated immunocompromised mice for ~12 months. The mice received exogenous human chorionic gonadotropin (hCG; 20IU, 3×/week). In xenografts exposed continuously to hCG, we demonstrate the maintenance of Leydig cell steroidogenesis, the acquisition of features of Sertoli cell maturation (androgen receptor, lumen development), and the formation of the blood–testis barrier (connexin 43), none of which were present prior to the transplantation or in xenografts in which hCG was withdrawn after 7 months. These studies provide evidence that hCG plays a role in Sertoli cell maturation, which is relevant for future investigations, helping them generate functional gametes from immature testis tissue for clinical application.

Download Full-text

Foxl2 Up-Regulates Aromatase Gene Transcription in a Female-Specific Manner by Binding to the Promoter as Well as Interacting with Ad4 Binding Protein/Steroidogenic Factor 1

Molecular Endocrinology ◽

10.1210/me.2006-0248 ◽

2007 ◽

Vol 21 (3) ◽

pp. 712-725 ◽

Cited By ~ 286

Author(s):

De-Shou Wang ◽

Tohru Kobayashi ◽

Lin-Yan Zhou ◽

Bindhu Paul-Prasanth ◽

Shigeho Ijiri ◽

...

Keyword(s):

Serum Levels ◽

Sex Reversal ◽

Dominant Negative ◽

Dominant Negative Mutant ◽

Testicular Development ◽

Aromatase Gene ◽

Ovarian Differentiation ◽

Forkhead Domain ◽

17Β Estradiol

Abstract Increasing evidence suggests the crucial role of estrogen in ovarian differentiation of nonmammalian vertebrates including fish. The present study has investigated the plausible role of Foxl2 in ovarian differentiation through transcriptional regulation of aromatase gene, using monosex fry of tilapia. Foxl2 expression is sexually dimorphic, like Cyp19a1, colocalizing with Cyp19a1 and Ad4BP/SF-1 in the stromal cells and interstitial cells in gonads of normal XX and sex-reversed XY fish, before the occurrence of morphological sex differentiation. Under in vitro conditions, Foxl2 binds to the sequence ACAAATA in the promoter region of the Cyp19a1 gene directly through its forkhead domain and activates the transcription of Cyp19a1 with its C terminus. Foxl2 can also interact through the forkhead domain with the ligand-binding domain of Ad4BP/SF-1 to form a heterodimer and enhance the Ad4BP/SF-1 mediated Cyp19a1 transcription. Disruption of endogenous Foxl2 in XX tilapia by overexpression of its dominant negative mutant (M3) induces varying degrees of testicular development with occasional sex reversal from ovary to testis. Such fish display reduced expression of Cyp19a1 as well as a drop in the serum levels of 17β-estradiol and 11-ketotestosterone. Although the XY fish with wild-type tilapia Foxl2 (tFoxl2) overexpression never exhibited a complete sex reversal, there were significant structural changes, such as tissue degeneration, somatic cell proliferation, and induction of aromatase, with increased serum levels of 17β-estradiol and 11-ketotestosterone. Altogether, these results suggest that Foxl2 plays a decisive role in the ovarian differentiation of the Nile tilapia by regulating aromatase expression and possibly the entire steroidogenic pathway.

Download Full-text

An overview of a Sertoli cell transplantation model to study testis morphogenesis and the role of the Sertoli cells in immune privilege

Environmental Epigenetics ◽

10.1093/eep/dvx012 ◽

2017 ◽

Vol 3 (3) ◽

Cited By ~ 4

Author(s):

Gurvinder Kaur ◽

Scott Vadala ◽

Jannette M. Dufour

Keyword(s):

Cell Transplantation ◽

Sertoli Cell ◽

Sertoli Cells ◽

Immune Privilege ◽

Transplantation Model

Download Full-text

Assays of testis development in the mouse distinguish three classes of domesticus-type Y chromosome

Genome ◽

10.1139/g88-140 ◽

1988 ◽

Vol 30 (6) ◽

pp. 870-878 ◽

Cited By ~ 30

Author(s):

Fred G. Biddle ◽

Yutaka Nishioka

Keyword(s):

Sex Determination ◽

Y Chromosome ◽

House Mouse ◽

Mus Musculus ◽

Autosomal Recessive ◽

Recessive Gene ◽

Laboratory Strain ◽

Sex Reversal ◽

Differential Interaction ◽

Y Chromosomes

The Y chromosome of Mus musculus poschiavinus interacts with the autosomal recessive gene tda-1b of the C57BL/6J laboratory strain of the house mouse to cause complete or partial sex reversal. Ovaries or ovotestes develop in a substantial proportion of the XY fetuses. Several different Y-specific DNA probes distinguish two major types of Y chromosome in the house mouse and they are represented by M. m. domesticus and M. m. musculus. The poschiavinus Y chromosome appears identical to the domesticus Y. The developmental distribution of the gonad types was examined in the first backcross or N2 generation of fetuses in C57BL/6J with six different domesticus-type Y chromosomes and, as controls, three different musculus-type Y chromosomes. Gonadal hermaphrodites were found with three of the six domesticus-type Y chromosomes. Both overall frequency and phenotypic distribution of types of gonadal hermaphrodites identify three classes of domesticus-type Y chromosome by their differential interaction with the C57BL/6J genetic background.Key words: mouse, Y chromosomes, gonadal hermaphrodites, primary sex determination.

Download Full-text