Normal testis determination in the mouse depends on genetic interaction of a locus on chromosome 17 and the Y chromosome.

Abstract We previously described a locus on chromosome (Chr) 17 of the mouse that is critical for normal testis development. This locus was designated "T-associated sex reversal" (Tas) because it segregated with the dominant brachyury allele hairpin tail (Thp) and caused gonads of C57BL/6J XY, Thp/+ individuals to develop as ovaries or ovotestes rather than as testes. To clarify the inheritance of Tas, we investigated the effects of T-Orleans (TOrl), another brachyury mutation, on gonad development. We found that gonads of C57BL/6J XY, Thp/+ and TOrl/+ mice develop ovarian tissue if the Y chromosome is derived from the AKR/J inbred strain, whereas normal testicular development occurs in the presence of a Y chromosome derived from the C57BL/6J inbred strain. From these observations we conclude that: (1) Tas is located in a region on Chr 17 common to the deletions associated with Thp, and TOrl, and (2) the Y-linked testis determining gene, Tdy, carried by the AKR/J inbred strain differs from that of the C57BL/6J inbred strain. We suggest that in mammals Tdy is not the sole testis determinant because autosomal loci must be genetically compatible with Tdy for normal testicular development.

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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.

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Autosomal genes involved in mammalian primary sex determination

Philosophical Transactions of the Royal Society of London Series B Biological Sciences ◽

10.1098/rstb.1988.0118 ◽

1988 ◽

Vol 322 (1208) ◽

pp. 109-118 ◽

Cited By ~ 27

Keyword(s):

Y Chromosome ◽

Ovarian Tissue ◽

Inbred Strains ◽

Chromosome 17 ◽

Mus Domesticus ◽

Inbred Strains Of Mice ◽

Testis Determination ◽

Two Populations ◽

T Locus ◽

Human Y Chromosome

Beginning with findings made during the late 1950s and early 1960s, evidence continues to accumulate in support of the hypothesis that the mammalian Y chromosome carries a gene that induces the undifferentiated foetal gonad in XY individuals to develop as a testis. Recently a DNA sequence has been isolated from the human Y chromosome that appears to be the hypothesized Y-linked testis-determining gene, and advances have also been made toward identifying genes that interact with the Y-linked testis-determining ( Tdy ) gene to initiate testis formation. These loci have been identified in specific stocks of mice carrying the mutant T hp or T orl allele at the T locus located on chromosome 17, and in crosses involving the transfer of a Y chromosome from two populations of Mus domesticus into the genomes of specific inbred strains of mice. The data in both cases support the hypothesis that there are several loci involved in testis determination and that abnormal interaction of these loci disrupts initiation of testis determination, resulting in development of ovarian tissue in XY individuals.

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Sex reversal in C57BL/6J-Y POS mice corrected by a Sry transgene

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.1995.0160 ◽

1995 ◽

Vol 350 (1333) ◽

pp. 263-269 ◽

Cited By ~ 43

Keyword(s):

Inbred Strain ◽

Y Chromosome ◽

Ovarian Tissue ◽

Testicular Tissue ◽

Gonadal Development ◽

Sex Reversal ◽

Dna Polymorphisms ◽

Mus Domesticus ◽

Y Chromosomes ◽

Strain Background

C57BL/6J mice carrying a Mus domesticus poschiavinus Y chromosome (Y POS ) develop as females with ovarian tissue or as hermaphrodites with ovarian and testicular tissue. We tested the hypothesis that the Y-linked component of this inherited sex reversal is caused by the M. d. poschiavinus Y-linked testis determining gene (symbolized Tdy or Sry ) by examining gonadal development in C57BL/6J XY POS mice carrying a M. musculus allele of Sry as a transgene. We found that in the presence of the transgene, XY POS mice developed exclusively testicular tissue. This result indicates that the Sry allele carried on the Y PDS chromosome is responsible for development of ovarian tissue in the G57BL/6J inbred strain background. We discuss this finding in light of DNA polymorphisms present in Sry alleles carried by various M. domesticus and M.musculus Y chromosomes. In addition, we present a hypothesis concerning the timing of expression of the testicular and ovarian determining genes in the developing fetal gonad based on the organization of ovarian and testicular tissue in ovotestes.

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C57BL/6J-T-Associated Sex Reversal in Mice Is Caused by Reduced Expression of a Mus domesticus Sry Allele

Genetics ◽

10.1093/genetics/158.4.1675 ◽

2001 ◽

Vol 158 (4) ◽

pp. 1675-1681 ◽

Cited By ~ 1

Author(s):

Linda L Washburn ◽

Kenneth H Albrecht ◽

Eva M Eicher

Keyword(s):

Sequence Analysis ◽

Y Chromosome ◽

Ovarian Development ◽

Inbred Strains ◽

Sex Reversal ◽

The Other ◽

Chromosome 17 ◽

Mus Domesticus ◽

Testis Development ◽

Normal Testis

Abstract C57BL/6J-T-associated sex reversal (B6-TAS) in XY mice results in ovarian development and involves (1) hemizygosity for Tas, a gene located in the region of Chromosome 17 deleted in Thp and TOrl, (2) homozygosity for one or more B6-derived autosomal genes, and (3) the presence of the AKR Y chromosome. Here we report results from experiments designed to investigate the Y chromosome component of this sex reversal. Testis development was restored in B6 TOrl/+XYAKR mice carrying a Mus musculus Sry transgene. In addition, two functionally different classes of M. domesticus Sry alleles were identified among eight standard and two wild-derived inbred strains. One class, which includes AKR, did not initiate normal testis development in B6 TOrl/+ XY mice, whereas the other did. DNA sequence analysis of the Sry ORF and a 5′ 800-bp segment divided these inbred strains into the same groups. Finally, we found that Sry is transcribed in B6 TOrl/+ XYAKR fetal gonads but at a reduced level. These results pinpoint Sry as the Y-linked component of B6-TAS. We hypothesize that the inability of specific M. domesticus Sry alleles to initiate normal testis development in B6 TOrl/+ XYAKR mice results from a biologically insufficient level of Sry expression, allowing the ovarian development pathway to proceed.

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Role of mammalian Y chromosome in sex determination

Philosophical Transactions of the Royal Society of London Series B Biological Sciences ◽

10.1098/rstb.1988.0114 ◽

1988 ◽

Vol 322 (1208) ◽

pp. 63-72 ◽

Cited By ~ 34

Keyword(s):

Cell Differentiation ◽

Sex Determination ◽

Y Chromosome ◽

Sertoli Cell ◽

Sertoli Cells ◽

Sex Reversal ◽

Testicular Development ◽

Chimeric Mouse ◽

Embryonic Gonad

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.

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The dominant white spotting oncogene allele Kit(W-42J) exacerbates XY(DOM) sex reversal

Development ◽

10.1242/dev.122.11.3597 ◽

1996 ◽

Vol 122 (11) ◽

pp. 3597-3605

Author(s):

C.M. Nagamine ◽

C. Carlisle

Keyword(s):

Inbred Strain ◽

Point Mutation ◽

Fetal Growth ◽

Sex Reversal ◽

Testis Size ◽

Rt Pcr ◽

Testis Differentiation ◽

Testis Determination ◽

Low Levels ◽

Almost All

The Y chromosome from certain populations of M. m. domesticus is incapable of normal testis determination in the B6 inbred strain resulting in XY hermaphrodites or XY females (XY(DOM) sex reversal). B6 consomic strains have been developed with either transient (B6-Y(AKR)) or severe (B6-Y(TIR)) XY(DOM) sex reversal. We report that a point mutation, the dominant white spotting oncogene allele, Kit(W-42J), exacerbates XY(DOM) sex reversal. In B6-Y(AKR), penetrance of the trait is low; however, in B6-Y(TIR), Kit(W-42J) exacerbated sex reversal to such an extent that almost all XY progeny developed into females. The exacerbation of sex reversal was not linked to retardation of early fetal growth or reduction of testis size. Furthermore, semiquantitative RT-PCR for the testis-determining gene, Sry, suggests that exacerbation of sex reversal in B6-Y(TIR) is not due to blockade of Sry expression, a substantial delay in initiation of Sry expression, or exceptionally low levels of Sry mRNAs. We propose that Kit(W-42J) enhances sex reversal by adversely affecting a critical step in testis differentiation that is downstream of Sry.

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The role of SOX9 in autosomal sex reversal and campomelic dysplasia

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.1995.0161 ◽

1995 ◽

Vol 350 (1333) ◽

pp. 271-278 ◽

Cited By ~ 18

Keyword(s):

Y Chromosome ◽

Chromosomal Rearrangements ◽

Sex Reversal ◽

Chromosome 17 ◽

Campomelic Dysplasia ◽

Skeletal Malformation ◽

Testis Development ◽

Human Chromosome 17 ◽

And Control

In eutherian mammals, the Y-chromosome gene SRY is required for induction of testis development. Although the Y chromosome is sex determining, loci located elsewhere in the genome participate in the complex cascade of genetic interactions required to form a testis. Male to female sex reversal (46,XY females) occurs at a high frequency in individuals afflicted with the skeletal malformation syndrome campomelic dysplasia. Chromosomal translocations in individuals with both syndromes had localized an autosomal sex reversal locus ( SRA1 ) and a campomelic dysplasia locus ( CMPD1 ) to the long arm of human chromosome 17. The molecular cloning of a translocation breakpoint in a sex reversed campomelic dysplasia patient revealed its proximity to SOX9 , a gene which is related to SRY . Analysis of SOX9 in patients without chromosomal rearrangements demonstrated single allele mutations in sex reversed campomelic individuals, linking this gene with both bone formation and control of testis development. Identification of SOX9 as SRA1 / CMPD1 and the role of SOX9 mutations in sex reversal and campomelic dysplasia are discussed.

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Efficient TALEN-mediated gene knockin at the bovine Y chromosome and generation of a sex-reversal bovine

Cellular and Molecular Life Sciences ◽

10.1007/s00018-021-03855-1 ◽

2021 ◽

Author(s):

Ming Wang ◽

ZhaoLin Sun ◽

Fangrong Ding ◽

Haiping Wang ◽

Ling Li ◽

...

Keyword(s):

Y Chromosome ◽

Nuclear Transfer ◽

Sex Reversal ◽

Practical Application ◽

Transcription Activator ◽

New Methods ◽

Fetal Fibroblasts ◽

Male Phenotype ◽

Solid Foundation ◽

First Time

AbstractFunctional elucidation of bovine Y-chromosome genes requires available genome editing technologies. Meanwhile, it has yet to be proven whether the bovine Sry gene is the main or single factor involved in the development of the male phenotype in bovine. Here, we efficiently knocked out four Y-linked genes (Sry, ZFY, DDX3Y, and EIF2S3Y) in bovine fetal fibroblasts (BFFs) with transcription activator-like effector nucleases (TALENs) individually. Furthermore, we used TALEN-mediated gene knockin at the Sry gene and generated a sex-reversal bovine by somatic cell nuclear transfer (SCNT). The resulting bovine had only one ovary and was sterile. We demonstrate, for the first time, that the Sry gene is an important sex-determining gene in bovine. Our method lays a solid foundation for detecting the biology of the bovine Y chromosome, as it may provide an alternative biological model system for the study of mammalian sex determination, and new methods for the practical application in agricultural, especially for sex predetermination.

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Defective Calmodulin-Mediated Nuclear Transport of the Sex-Determining Region of the Y Chromosome (SRY) in XY Sex Reversal

Molecular Endocrinology ◽

10.1210/me.2004-0334 ◽

2005 ◽

Vol 19 (7) ◽

pp. 1884-1892 ◽

Cited By ~ 39

Author(s):

Helena Sim ◽

Kieran Rimmer ◽

Sabine Kelly ◽

Louisa M. Ludbrook ◽

Andrew H. A. Clayton ◽

...

Keyword(s):

Y Chromosome ◽

Nuclear Import ◽

High Mobility ◽

Sex Reversal ◽

High Mobility Group ◽

Missense Mutations ◽

Nuclear Localization Signals ◽

Xy Sex Reversal

Abstract The sex-determining region of the Y chromosome (SRY) plays a key role in human sex determination, as mutations in SRY can cause XY sex reversal. Although some SRY missense mutations affect DNA binding and bending activities, it is unclear how others contribute to disease. The high mobility group domain of SRY has two nuclear localization signals (NLS). Sex-reversing mutations in the NLSs affect nuclear import in some patients, associated with defective importin-β binding to the C-terminal NLS (c-NLS), whereas in others, importin-β recognition is normal, suggesting the existence of an importin-β-independent nuclear import pathway. The SRY N-terminal NLS (n-NLS) binds calmodulin (CaM) in vitro, and here we show that this protein interaction is reduced in vivo by calmidazolium, a CaM antagonist. In calmidazolium-treated cells, the dramatic reduction in nuclear entry of SRY and an SRY-c-NLS mutant was not observed for two SRY-n-NLS mutants. Fluorescence spectroscopy studies reveal an unusual conformation of SRY.CaM complexes formed by the two n-NLS mutants. Thus, CaM may be involved directly in SRY nuclear import during gonadal development, and disruption of SRY.CaM recognition could underlie XY sex reversal. Given that the CaM-binding region of SRY is well-conserved among high mobility group box proteins, CaM-dependent nuclear import may underlie additional disease states.

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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.

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