title: WNT4 and RSPO1 together are required for cell proliferation in the early mouse gonad.
abstract: The gonad arises from the thickening of the coelomic epithelium and then commits into the sex determination process. Testis differentiation is activated by the expression of the Y-linked gene Sry, which promotes cell proliferation and differentiation of Sertoli cells, the supporting cells of the testis. In absence of Sry (XX individuals), activation of WNT/CTNNB1 signalling, via the upregulation of Rspo1 and Wnt4, promotes ovarian differentiation. However, Rspo1 and Wnt4 are expressed in the early undifferentiated gonad of both sexes, and Axin2-lacZ, a reporter of canonical WNT/CTNNB1 signalling, is expressed in the coelomic region of the E11.5 gonadal primordium, suggesting a role of these factors in early gonadal development. Here, we show that simultaneous ablation of Rspo1 and Wnt4 impairs proliferation of the cells of the coelomic epithelium, reducing the number of progenitors of Sertoli cells in XY mutant gonads. As a consequence, in XY Wnt4(-/-); Rspo1(-/-) foetuses, this leads to the differentiation of a reduced number of Sertoli cells and the formation of a hypoplastic testis exhibiting few seminiferous tubules. Hence, this study identifies Rspo1 and Wnt4 as two new regulators of cell proliferation in the early gonad regardless of its sex, in addition to the specific role of these genes in ovarian differentiation.
authors.affiliation: Université de Nice-Sophia Antipolis, F-06108 Nice,  France.
authors.forename: Anne-Amandine
authors.initials: AA
authors.lastname: Chassot
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Bradford
authors.forename: Aurélie
authors.initials: A
authors.lastname: Auguste
authors.forename: Elodie P
authors.initials: EP
authors.lastname: Gregoire
authors.forename: Eric
authors.initials: E
authors.lastname: Pailhoux
authors.forename: Dirk G
authors.initials: DG
authors.lastname: de Rooij
authors.forename: Andreas
authors.initials: A
authors.lastname: Schedl
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Chaboissier
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D049109:Cell Proliferation; D005260:Female; D006066:Gonads / Q000196:embryology* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010053:Ovary / Q000196:embryology; D055758:SOX9 Transcription Factor / Q000096:biosynthesis; D012708:Sertoli Cells / Q000378:metabolism; D019849:Sex Determination Processes; D015398:Signal Transduction; D013737:Testis / Q000196:embryology; D019699:Thrombospondins / Q000235:genetics / Q000378:metabolism*; D060528:Wnt4 Protein / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
chemical_list: C495267:CTNNB1 protein, mouse; C518903:RSPO1 protein, mouse; D055758:SOX9 Transcription Factor; C527933:Sox9 protein, mouse; D019699:Thrombospondins; D060528:Wnt4 Protein; C555582:Wnt4 protein, mouse; D051176:beta Catenin