Molecular Characterization of XX Maleness

Abstract

Androgens and anti-Müllerian hormone (AMH), secreted by the foetal testis, are responsible for the development of male reproductive organs and the regression of female anlagen. Virilization of the reproductive tract in association with the absence of Müllerian derivatives in the XX foetus implies the existence of testicular tissue, which can occur in the presence or absence of SRY. Recent advancement in the knowledge of the opposing gene cascades driving to the differentiation of the gonadal ridge into testes or ovaries during early foetal development has provided insight into the molecular explanation of XX maleness.

Keywords: disorders of sex development; ovary; testis.

Figure 1

Sex differentiation during embryonic and foetal life in mammals: the mesonephros and the coelomic epithelium are stabilized and their cells proliferate, in response to the action of GATA4, EMX2, CBX2, LHX9 and WT1 -which upregulate SF1-, SIX1 and SIX4, TCF21 and members of the IGF family, to form the undifferentiated gonad. In XY foetuses, SRY expression is triggered by MAP3K4, GATA4, JMJDA1, WT1 and SF1; SRY upregulates SOX9 and other SOX family members. SOX9, PGD2 and FGF9 establish a positive feed-forward loop, which increases SOX9 expression, which prevails over DAX1, FOXL2, WNT4 and RSPO1, thus promoting testicular differentiation. The developing testis secretes testosterone and anti-Müllerian hormone (AMH), responsible for male differentiation of internal and external genitalia; testosterone can be transformed into dihydrotestosterone (DHT), a more potent androgen, through the action of the enzyme 5α-reductase (5α-Red); both testosterone and DHT act on the same androgen receptor (AR). In the XX foetuses, due to the absence of SRY, SOX9 expression remains low and is overcome by DAX1, FOXL2, WNT4 and RSPO1, which upregulate β-catenin; a feed-forward loop between these pro-ovarian factors is established, resulting in the differentiation of the female gonad. Since the ovary does not secrete androgens and AMH, internal and external genitalia develop through the female pathway. Modified with permission from Rey and Grinspon, 2011 [5]. Copyright 2010 Elsevier Ltd.

Figure 2

Testicular and ovotesticular differentiation in XX foetuses. In individuals with Yp translocations, the presence of SRY triggers testicular differentiation (SRY-positive cases). In SRY-negative individuals, testicular development may result from overexpression of “pro-testicular” factors (e.g., SOX9, SOX3, SOX10, FGF9, DMRT1) due to duplications/triplications of gene coding or regulatory sequences, or from inactivating mutations of “pro-ovarian” factors (e.g., RSPO1, WNT4, FOXL2) or factors that are believed to favour the gene dosage balance through the ovarian pathway (WT1, SF1, COUP-TF2). Generally, though not always, testicular DSD presents with male genitalia and ovotesticular DSD with ambiguous genitalia.