ESPE Yearbook of Paediatric Endocrinology

To read the full abstract: Sex Dev. 2017;11(5-6):269-274

[Comments on 6.11, 6.12 and 6.13] Evidence for factors necessary for female sexual development are presented in the above 3 publications. Studies of 46,XX DSD individuals show compiling evidence for factors necessary for female development and to counteract male development. The paradigm that female development is the default pathway has proven to be untrue. Studies of individuals with 46,XX DSD have revealed more factors and proof for active processes necessary for the female development.

First, Zhao et al. (6.11) report on studies on mice that challenge the notion that the Wolffian ducts regress if simply unexposed to androgens. They show that the nuclear receptor COUP-TF2 in the mouse is necessary for elimination of Wolffian ducts. An enhanced kinase signaling seems to be involved, possibly regulated via androgens.

Second, Bashamboo et al. (6.12) report the first evidence COUP-TF2 is necessary for uncompromised ovarian development in humans. A mutation in the gene resulted in formation of testis tissue and androgen production in 3 individuals with 46,XX karyotype. The findings indicate that nuclear receptors may have divergent functions affecting the heart and genitalia. They show that COUP-TF2 is a “pro-ovary” and “anti-testis” sex-determining factor in human female gonads. Importantly, COUP-TF2 seems to be the underlying theme of pro-female and anti-male function in both mice and humans. There is emerging evidence that nuclear receptors are important in human ovarian development and that nuclear receptors have divergent functions in both mouse and human biology.

Thirdly, Naasse et al. (6.13) report a missense mutation in the RSPO-1 gene in 2 siblings with 46,XX testicular DSD and ovotesticular DSD. This study establishes the importance of RSPO-1 for female ovarian development. In ovarian differentiation, upregulation of WNT4 is initially promoted by RPSO-1 expression. Lack of RSPO-1 enables the gonad to develop along the testis pathway resulting in testicular DSD with male gender, and ovotesticular DSD with female gender in the two siblings, respectively. Similar to previous cases with RSPO-1 mutations, the siblings had palmoplantar keratoderma, and in addition, hearing deficits related to the role of R-spondins as activators of both WNT/CTNNB1 and WNT/planar cell polarity (PCP) in signaling in cell differentiation and cancer. Interestingly, in mice, both Rspo1 and Wnt4 are regulators of cell proliferation in the early gonad regardless of its sex. Simultaneous ablation of Rspo1 and Wnt4 impairs proliferation of cells of the coelomic epithelium, and leads to the differentiation of a reduced number of Sertoli cells and the formation of hypoplastic testes with few seminiferous tubules (see Chassot et al.). Moreover, mutations in WNT4 have been found to cause Mayer-Rokitansky-Küster-Hauser syndrome in a small subgroup of patients with signs of hyperandrogenaemia (see Ledig et al.). Hence, both RSPO-1 and WNT4 are important players in multiple steps in differentiation and development. Our knowledge and understanding of the complexity of the different factors involved in sex development is increasing. Studies of individuals with syndromic forms of DSD have contributed important pieces of information in the past and will probably continue to do so in the future.

Chassot AA, Bradford ST, Auguste A, Gregoire EP, Pailhoux E, de Rooij DG, Schedl A, Chaboissier MC. WNT4 and RSPO1 together are required for cell proliferation in the early mouse gonad. Development. 2012;139(23):4461-72.

Ledig S, Wieacker P. Clinical and genetic aspects of Mayer-Rokitansky-Küster-Hauser syndrome. Med Genet. 2018;30(1):3-11. doi: 10.1007/s11825-018-0173-7. Review.