A timeline of the major cellular events in testis and ovary morphogenesis. During mouse embryogenesis, the bipotential gonad is formed around 10.5 dpc. Sry is expressed from the Y chromosome beginning at 10.5 dpc in the XY gonad (top, blue) and its expression triggers the first step of testis morphogenesis (1), specification of the Sertoli cell lineage. By 12.5 dpc, the testes have compartmentalized to form defined cord structures surrounded by a basal lamina (2). This step is driven by the migration of endothelial cells into the gonad and involves the recruitment of PTM cells to surround the cords. The final stage (3) of testis development is testis cord elongation, which transforms simple loops into a convoluted tubule structure. In the XX gonad, where Sry is absent (bottom, pink), events in testis morphogenesis do not happen. Specification of the granulosa cell lineage defines step 1 of ovary organogenesis (1). Female germ cells within the germ cell nest begin to enter meiosis at 13.5 dpc and arrest in the diplotene stage of meiosis I beginning at 17.5 dpc. The germ cell nests break down soon after birth (2) when granulosa cells invade the nest and surround individual oocytes to form primordial follicles. Follicle activation compartmentalizes the somatic cell environment during the first week of postnatal life (3), accompanied by the recruitment of theca cells to the primary follicle.

Mechanisms of Sertoli cell expansion. Two waves of Sertoli cell expansion occur during testis morphogenesis. A Sertoli cell progenitors undergo the first wave of expansion in response to an autoregulatory feedback loop initiated by SRY. SRY induces the expression of Sox9, which promotes the production of FGF9 and PGD2. These 2 factors activate their respective receptors (FGFR2 and DP, respectively) on neighboring pre-Sertoli cells to form positive feedback loops that maintain SOX9 expression and stimulate Sertoli cell proliferation. B The second wave of Sertoli cell expansion in the mouse testis occurs after 15.5 dpc. This expansion is triggered by Leydig cell-derived activin A, which induces Sertoli cell proliferation via SMAD4.

Mechanisms of endothelial cell migration and testis cord formation. A At 11.5 dpc, there is minimal vasculature in the testis, but a prominent vessel structure, the mesonephric vascular plexus (MVP), is present in the neighboring mesonephros. 12 h later, the MVP breaks down and individual endothelial cells are observed to migrate into the testis, towards the coelomic domain. By 12.5 dpc, the coelomic vessel is clearly visible at the coelomic domain of the testis and testis cords have formed along the tracks followed by the migrating endothelial cells. B At the molecular level, SRY and its downstream effector SOX9 control sexually dimorphic vascularization of the gonad. In the XY gonad (right) SRY/SOX9 suppress Wnt4 and its downstream target Fst. In the absence of WNT4/FST, activin B becomes available and along with other possible factors, including VEGF, promotes vascularization of the testis. When SRY/SOX9 are absent, such as in the ovary (left), the inhibition on Wnt4 and Fst is relieved. WNT4/FST therefore repress the activity of activin B and subsequently prevent the testis pattern of vascularization.

Establishment of the theca cell lineage. Theca cells are recruited to primordial follicles during the first week of postnatal life. The origins of theca progenitor cells are currently not known; 2 possible sources, the mesonephros and the ovarian stroma, are labeled with question marks. Following primordial follicle activation, the oocyte and/or somatic cells of the follicle produce factors that promote the differentiation and migration of theca progenitor cells. Multiple stages of follicle development are illustrated, ranging from primordial follicle (A) to primary follicle (B).