Male sex determination: insights into molecular mechanisms

Abstract

Disorders of sex development often arise from anomalies in the molecular or cellular networks that guide the differentiation of the embryonic gonad into either a testis or an ovary, two functionally distinct organs. The activation of the Y-linked gene Sry (sex-determining region Y) and its downstream target Sox9 (Sry box-containing gene 9) triggers testis differentiation by stimulating the differentiation of Sertoli cells, which then direct testis morphogenesis. Once engaged, a genetic pathway promotes the testis development while actively suppressing genes involved in ovarian development. This review focuses on the events of testis determination and the struggle to maintain male fate in the face of antagonistic pressure from the underlying female programme.

Gonadotrope-specific Deletion of Dicer Results in Severely Suppressed Gonadotropins and Fertility Defects

“…5G). The transcription factor SOX9 is expressed downstream of SRY, the testis determining factor, and defines the Sertoli cell lineage in the testis (81)(82)(83). The expression of SOX9 did not change irrespective of whether the male fertility was moderately or severely affected in Dicer cKO mutant mice (Fig.…”

Structure-Function Relationships in Human Testis-determining Factor SRY

“…7 The integrated intensity of the Trp fluorescence emission spectrum of the WT complex at 15°C was 2-fold less than that of the free domain, providing evidence for the quenching of one or more Trp side chains; such quenching is presumably due to stabilization of the domain on specific DNA binding leading to more complete desolvation of its hydrophobic core. In accordance with this interpretation, the maximum of the native WT spectrum (355 mm) was blue-shifted relative to its max in 8 M guanidine (364 nm, data not shown).…”

“…Unlike the free domains, however, relative intensities in the variant DNA complexes correlated with side-chain volume (W70A Ͼ W70L). In all cases, 7 The contribution of Trp-107 to the WT fluorescence spectrum was inferred from comparison of the WT domain and a W107D variant (data not shown).…”

“…Expression of Sox9 in turn regulates a gene-regulatory network (GRN) that distinguishes between testicular and ovarian programs of gonadogenesis (5). Hormones secreted by the fetal testis, once formed, direct regression of female primordia (Müllerian inhibiting substance/anti-Müllerian hormone; MIS/AMH) (6) and external virilization (testosterone) (7). Clinical mutations in this pathway, including in the genes encoding SRY, SOX9, MIS/AMH, and the androgen receptor, are associated with disorders of sexual differentiation (DSD) (8).…”

Regulation of meiotic entry and gonadal sex differentiation in the human: normal and disrupted signaling

“…In mice, DAZL is involved in rendering the germ cells competent to enter meiosis and could be the intrinsic signal necessary to initiate meiosis (34). In fetal mouse testes, RAmediated initiation of meiosis is prevented by the action of the RA-degrading enzyme CYP26B1 (1, 2) and subsequently by NANOS2 (3), FGF9 (35,36), DMRT1 (4), and NODAL (37,38). In 2011, the model for RA-induced meiosis was challenged by Kumar et al (39), who found Stra8 expression in fetal ovaries from mice lacking RA synthesis (Raldh -/-) in mesonephros and gonads, thereby suggesting that RA is not the only inducer of Stra8 expression and meiosis.…”