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To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ydbio.2008.10.040 Byline: Alexander N. Combes (a), Dagmar Wilhelm (a), Tara Davidson (a), Elisabetta Dejana (b), Vincent Harley (c), Andrew Sinclair (d), Peter Koopman (a) Keywords: Organogenesis; Cell migration; Testis development; Endothelial cells; Organ culture; Imaging Abstract: While the molecular cues initiating testis determination have been identified in mammals, the cellular interactions involved in generating a functional testis with cord and interstitial compartments remain poorly understood. Previous studies have shown that testis cord formation relies on cell migration from the adjacent mesonephros, and have implicated immigrant peritubular myoid cells in this process. Here, we used recombinant organ culture experiments to show that immigrant cells are endothelial, not peritubular myoid or other interstitial cells. Inhibition of endothelial cell migration and vascular organisation using a blocking antibody to VE-cadherin, also disrupted the development of testis cords. Our data reveal that migration of endothelial cells is required for testis cord formation, consistent with increasing evidence of a broader role for endothelial cells in establishing tissue architecture during organogenesis. Author Affiliation: (a) Division of Molecular Genetics and Development, Institute for Molecular Biosciences, The University of Queensland, Brisbane, QLD 4072, Australia (b) IFOM, FIRC Institute of Molecular Oncology, Via Adamello 16, 20139 Milan, Italy (c) Prince Henry's Institute of Medical Research, Melbourne, VIC 3168, Australia (d) Murdoch Children's Research Institute and Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Melbourne, VIC 3052, Australia Article History: Received 12 August 2008; Revised 7 October 2008; Accepted 27 October 2008

The sex determination process in mammals, for long described as a male determination process, is challenged by the discovery that the gene encoding R-spondin1 is mutated in human patients with female-to-male sex reversal. The possible roles of R-spondin1 during sex determination are discussed.

I. Introduction II. The Chromosomal Basis of Mammalian Sex Determination III. Morphology and Cell Biology of the Developing Gonad A. The bipotential gonad B. Development and differentiation of the ductal [...]

We have raised an antibody specifically recognizing endogenous mouse SRY protein and used it to investigate the molecular and cellular mode of action of SRY in testis determination. We find that expression of SRY protein closely mirrors the expression of Sry mRNA in mouse genital ridges and is detectable for 6 to 8 h after the mRNA ceases to be detectable. The subset of somatic cells that expresses SRY begins to express SOX9 almost immediately. Since these SOX9-positive cells go on to develop as Sertoli cells, it appears that SRY expression marks the pre-Sertoli cell lineage and leads to up-regulation of Sox9 expression cell-autonomously. However, a small proportion of SOX9-positive cells did not appear to express SRY, possibly reflecting the additional involvement of paracrine signaling in activating Sox9 transcription in these cells. We confirmed by ex vivo cell mixing experiments that SRY is able to engage receptor-mediated signaling to up-regulate Sox9 expression. Finally, we showed by employing specific inhibitors that the causative signaling molecule is prostaglandin D2 (PGD2) and that PGD2 can induce Sox9 transcription in cultured XX gonads. Our data indicate a mechanism whereby Sry uses both a cell-autonomous mechanism and a PGDz-mediated signaling mechanism to stimulate expression of Sox9 and induce the differentiation of Sertoli cells in vivo. Keywords: SRY; Sox9; Gonad development; Sex determination; Testis differentiation; Prostaglandin; Sertoli cell

Research has been conducted on Wilms tumor suppressor WT1 gene. Results indicate that WT1 and the Lim homeobox gene are direct activators of the gene encoding steroidogenic factor 1 and thus mediate early gonadogenesis.