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During mammalian development, gonadal sex determination results from the commitment of bipotential supporting cells to Sertoli or granulosa cell fates. Typically, this decision is coordinated across the gonad to ensure commitment to a single organ fate. When unified commitment fails in an XY mouse, an ovotestis forms in which supporting cells in the center of the gonad typically develop as Sertoli cells, while supporting cells in the poles develop as granulosa cells. This central bias for Sertoli cell fate was thought to result from the initial expression of the drivers of Sertoli cell fate, SRY and/or SOX9, in the central domain, followed by paracrine expansion to the poles. However, we show here that the earliest cells expressing SRY and SOX9 are widely distributed across the gonad. In addition, Sertoli cell fate does not spread among supporting cells through paracrine relay. Instead, we uncover a center-biased pattern of supporting cell precursor ingression that occurs in both sexes and results in increased supporting cell density in the central domain. Our findings prompt a new model of gonad patterning in which a density-dependent organizing principle dominates Sertoli cell fate stabilization. [ABSTRACT FROM AUTHOR]

On Thursday 9 May 1991, the world awoke to front-page news of a breakthrough in biological research. FromWashington toWollongong, newspapers, radio and TV were abuzz with the story of a transgenic mouse in London called Randy. Why was this mouse so special? The mouse in question was a chromosomal female (XX) made male by the presence of a transgene containing the Y chromosome gene Sry. This sex-reversal provided clear experimental proof that Sry was the elusive mammalian sex-determining gene. Twenty-five years on, we reflect on what this discovery meant for our understanding of how males and females arise and what remains to be understood. [ABSTRACT FROM AUTHOR]

Mammalian sex determination hinges on the development of ovaries or testes, with testis fate being triggered by the expression of the transcription factor sex-determining region Y (Sry). Reduced or delayed Sry expression impairs testis development, highlighting the importance of its accurate spatiotemporal regulation and implying a potential role for SRY dysregulation in human intersex disorders. Several epigenetic modifiers, transcription factors and kinases are implicated in regulating Sry transcription, but it remains unclear whether or how this farrago of factors acts co-ordinately. Here we review our current understanding of Sry regulation and provide a model that assembles all known regulators into three modules, each converging on a single transcription factor that binds to the Sry promoter. We also discuss potential future avenues for discovering the cis-elements and trans-factors required for Sry regulation. [ABSTRACT FROM AUTHOR]

The nuclear receptor transcription factor Dax1 is hypothesized to play a role in testicular development, although the mechanism of its action is unknown. Here, we present evidence that Dax1 plays an early essential role in fetal testis development. We hypothesize that upregulation of Sox9 expression in precursor somatic cells, a process required for their differentiation as Sertoli cells, depends on the coordinated expression of Dax1, Sry and another gene, Tda1. Our conclusion and model are based on the following experimental findings: (1) presence of a mutant Dax1 allele (Dax1-) results in complete gonadal sex reversal in C57BL/6JEi (B6) XY mice, whereas testes develop in DBA/2J (D2) and (B6xD2)F1 XY mice; (2) B6-DAX1 sex reversal is inherited as a complex trait that includes the chromosome 4 gene Tda1; (3) B6 Dax1-/Y fetal gonads initiate development as ovaries, even though Sry expression is activated at the correct time and at appropriate levels; (4) upregulation of Sox9 does not occur in B6 Dax1-/Y fetal gonads in spite of apparently normal Sry expression; and (5) overexpression of Sry in B6 Dax1-/Y fetal gonads upregulates Sox9 and corrects testis development. [ABSTRACT FROM AUTHOR]

Recently, we demonstrated that loss of Fgf9 results in a block of testis development and a male to female sex-reversed phenotype; however, the function of Fgf9 in sex determination was unknown. We now show that Fgf9 is necessary for two steps of testis development just downstream of the male sex-determining gene, Sry: (1) for the proliferation of a population of cells that give rise to Sertoli progenitors; and (2) for the nuclear localization of an FGF receptor (FGFR2) in Sertoli cell precursors. The nuclear localization of FGFR2 coincides with the initiation of Sry expression and the nuclear localization of SOX9 during the early differentiation of Sertoli calls and the determination of male fate. [ABSTRACT FROM AUTHOR]

Development of myelin-forming oligodendrocytes in the central nervous system is dependent on at least two members of the Sox family of high-mobility-group-containing transcription factors. Sox9 is involved in oligodendrocyte specification, whereas Sox10 is required for terminal differentiation. We show that oligodendrocytes in the spinal cord additionally express the highly related Sox8. In Sox8-deficient mice, oligodendrocyte development proceeded normally until birth. However, terminal differentiation of oligodendrocytes was transiently delayed at early postnatal times. Sox8-deficient mice thus exhibited a similar, but less severe phenotype than did Sox10-deficient mice. Terminal oligodendrocyte differentiation was dramatically delayed in Sox8-deficient mice with only a single functional Sox10 allele hinting at redundancy between both Sox proteins. This redundancy was also evident from the fact that Sox8 bound to naturally occurring Sox10 response elements, was able to form DNA-dependent heterodimers with Sox10 and activated Sox10-specific oligodendrocytic target genes in a manner similar to Sox10. However, Sox8 expression levels were significantly lower than those for Sox10. Resulting differences in protein amounts might be a main reason for the weaker impact of Sox8 on oligodendrocyte development and for unidirectional compensation of the Sox8 loss by Sox10. [ABSTRACT FROM AUTHOR]

The developmental fate of primordial germ cells in the mammalian gonad depends on their environment. In the XY gonad, Sry induces a cascade of molecular and cellular events leading to the organization of testis cords. Germ cells are sequestered inside testis cords by 12.5 dpc where they arrest in mitosis. If the testis pathway is not initiated, germ cells spontaneously enter meiosis by 13.5 dpc, and the gonad follows the ovarian fate. We have previously shown that some testis-specific events, such as mesonephric cell migration, can be experimentally induced into XX gonads prior to 12.5 dpc. However, after that time, XX gonads are resistant to the induction of cell migration. In current experiments, we provide evidence that this effect is dependent on XX germ cells rather than on XX somatic cells. We show that, although mesonephric cell migration cannot be induced into normal XX gonads at 14.5 dpc, it can be induced into XX gonads depleted of germ cells. We also show that when 14.5 dpc XX somatic cells are recombined with XY somatic cells, testis cord structures form normally; however, when XX germ cells are recombined with XY somatic cells, cord structures are disrupted. Sandwich culture experiments suggest that the inhibitory effect of XX germ cells is mediated through short-range interactions rather than through a long-range diffusible factor. The developmental stage at which XX germ cells show a disruptive effect on the male pathway is the stage at which meiosis is normally initiated, based on the immunodetection of meiotic markers. We suggest that at the stage when germ cells commit to meiosis, they reinforce ovarian fate by antagonizing the testis pathway. [ABSTRACT FROM AUTHOR]

An abstract of a research paper by Kenichi Kashimada and Peter Koopman, related to a mammalian Y-chromosomal testis-determining gene called SRY, is presented.

In mammals, the Y-linked sex-determining gene Sry cell-autonomously promotes Sertoli cell differentiation from bipotential supporting cell precursors through SRY-box containing gene 9 (Sox9), leading to testis formation. Without Sry action, the supporting cells differentiate into granulosa cells, resulting in ovarian development. However, how Sry acts spatiotemporally to switch supporting cells from the female to the male pathway is poorly understood. We created a novel transgenic mouse line bearing an inducible Sry transgene under the control of the Hsp70.3 promoter. Analysis of these mice demonstrated that the ability of Sry to induce testis development is limited to approximately 11.0-11.25 dpc, corresponding to a time window of only 6 hours after the normal onset of Sry expression in XY gonads. If Sry was activated after 11.3 dpc, Sox9 activation was not maintained, resulting in ovarian development. This time window is delimited by the ability to engage the high-FGF9/low-WNT4 signaling states required for Sertoli cell establishment and cord organization. Our results indicate the overarching importance of Sry action in the initial 6-hour phase for the female-to-male switching of FGF9/WNT4 signaling patterns. [ABSTRACT FROM AUTHOR]

Specification of the myelin-forming oligodendrocytes of the central nervous system requires the Sox9 transcription factor, whereas terminal differentiation depends on the closely related Sox10. Between specification and terminal differentiation, Sox9 and Sox10 are co-expressed in oligodendrocyte precursors and are believed to exert additional functions. To identify such functions, we have deleted Sox9 specifically in already specified oligodendrocyte precursors of the spinal cord. In the absence of Sox9, oligodendrocyte precursors developed normally and started terminal differentiation on schedule. However, when Sox10 was additionally deleted, oligodendrocyte precursors exhibited an altered migration pattern and were present in reduced numbers because of increased apoptosis rates. Remaining precursors continued to express many characteristic oligodendroglial markers. Aberrant expression of astrocytic and neuronal markers was not observed. Strikingly, we failed to detect PDGF receptor α expression in the mutant oligodendrocyte precursors, arguing that PDGF receptor α is under transcriptional control of Sox9 and Sox10. Altered PDGF receptor α expression is furthermore sufficient to explain the observed phenotype, as PDGF is both an important survival factor and migratory cue for oligodendrocyte precursors. We thus conclude that Sox9 and Sox10 are required in a functionally redundant manner in oligodendrocyte precursors for PDGF-dependent survival and migration. [ABSTRACT FROM AUTHOR]

The transcription factor Sox10 regulates early neural crest development, specification of neural crest-derived lineages and terminal differentiation of oligodendrocytes in the central nervous system. Here, we generated two novel hypomorphic Sox10 alleles in the mouse. Mutant mice either expressed a Sox10 protein with a triple alanine substitution in the dimerization domain, or a Sox10 protein with a deletion in the central portion that we define as a cell-specific transactivation domain. Phenotypic analysis revealed important roles for a functional dimerization domain and the newly defined novel transactivation domain in melanocyte and enteric nervous system development, whereas early neural crest development and oligodendrocyte differentiation were surprisingly little disturbed in both mutants. Unique requirements were additionally detected for the novel transactivation domain in satellite glia differentiation and during Schwann cell myelination, whereas DNA-dependent dimerization was needed for immature Schwann cells to enter the promyelinating stage. These two hypomorphic alleles thus uncover novel functions of Sox10 in satellite glia and Schwann cells during late developmental stages and reveal important developmental differences between these two types of peripheral glia and oligodendrocytes regarding their reliance on Sox10. [ABSTRACT FROM AUTHOR]

The sex-determining region of Chr Y (Sry) gene is sufficient to induce testis formation and the subsequent male development of internal and external genitalia in chromosomally female mice and humans. In XX sex-reversed males, such as XX/Sry-transgenic (XX/Sry) mice, however, testicular germ cells always disappear soon after birth because of germ cell-autonomous defects. Therefore, it remains unclear whether or not Sry alone is sufficient to induce a fully functional testicular soma capable of supporting complete spermatogenesis in the XX body. Here, we demonstrate that the testicular somatic environment of XX/Sry males is defective in supporting the later phases of spermatogenesis. Spermatogonial transplantation analyses using XX/Sry male mice revealed that donor XY spermatogonia are capable of proliferating, of entering meiosis and of differentiating to the round-spermatid stage. XY-donor-derived round spermatids, however, were frequently detached from the XX/Sry seminiferous epithelia and underwent cell death, resulting in severe deficiency of elongated spermatid stages. By contrast, immature XY seminiferous tubule segments transplanted under XX/Sry testis capsules clearly displayed proper differentiation into elongated spermatids in the transplanted XY-donor tubules. Microarray analysis of seminiferous tubules isolated from XX/Sry testes confirmed the missing expression of several Y-linked genes and the alterations in the expression profile of genes associated with spermiogenesis. Therefore, our findings indicate dysfunction of the somatic tubule components, probably Sertoli cells, of XX/Sry testes, highlighting the idea that Sry alone is insufficient to induce a fully functional Sertoli cell in XX mice. [ABSTRACT FROM AUTHOR]

Sox8 and Sox10 are two closely related transcription factors of the Sox protein family with overlapping expression patterns during development. They are believed to perform very similar functions because several developmental processes, including enteric nervous system development and oligodendrocyte differentiation, are regulated by both Sox proteins. To analyze the extent of functional equivalence between the two Sox proteins, we employed targeted mutagenesis to replace Sox10 with Sox8 in the mouse. In mice that expressed Sox8 instead of Sox10, Sox10 deficiency was phenotypically rescued to different extents in affected tissues. Whereas development of glial cells and neurons in the sensory and sympathetic parts of the peripheral nervous system was almost normal when Sox10 was replaced by Sox8, melanocyte development was as defective as in Sox10-deficient mice. The ability of Sox8 to rescue the defects in enteric nervous system development and oligodendrocyte differentiation of Sox10-deficient mice was limited. We conclude that the extent of functional equivalence depends on the tissue and that, despite their relatedness, Sox8 and Sox10 have more unique functions than previously appreciated. [ABSTRACT FROM AUTHOR]