Sfrp1 and Sfrp2 are required for normal male sexual development in mice

Abstract

Secreted frizzled-related proteins (Sfrps) are antagonists of WNT signalling implicated in a variety of biological processes. However, there are no reports of a direct role for Sfrps in embryonic organogenesis in mammals. Using in vivo loss-of-function studies we report here for the first time a redundant role for Sfrp1 and Sfrp2 in embryonic sexual development of the mouse. At 16.5 dpc, male embryos lacking both genes exhibit multiple defects in gonad morphology, reproductive tract maturation and gonad positioning. Abnormal positioning of the testis appears to be due to failed gubernaculum development and an unusually close association between the cranial end of the reproductive tract and the kidney. The testes of double homozygotes are smaller than controls, contain fewer cords from the earliest stages, but still express Insl3, which encodes the hormone required for gubernacular masculinisation. Lgr8, which encodes the Insl3 receptor, is also expressed in the mutant gubernaculum, suggesting that Sfrp1/Sfrp2 signalling is not required for expression of the ligand or receptor that controls transabdominal testicular descent. Similarities between the abnormalities of embryonic sexual development in Sfrp1(-/-)Sfrp2(-/-) embryos with those exhibited by the Looptail and Wnt5a mutants suggest that disrupted non-canonical Wnt signalling may cause these defects.

Expression and Functional Analysis of Dkk1 during Early Gonadal Development

“…Male-specific expression of other (mechanistically different) antagonists of WNT signalling, Sfrp1 and Sfrp2 [Warr et al, 2009], may compensate for the lack of Dkk1 . Testes are smaller and have fewer cords in compound mutants lacking Sfrp1 and Sfrp2 [Warr et al, 2009], leaving open the possibility of redundancy between Dkk1 and the Sfrp genes. However, this possibility remains to be tested by analysing doubleor triple-knockout mice.…”

Secreted and Transmembrane Wnt Inhibitors and Activators

“…In addition to the role in regulating AP-axis elongation and somitogenesis during mouse development, Sfrp1 and -2 exert redundant roles also in embryonic organogenesis, as both genes are required for normal male sexual development in mice (Warr et al 2009). …”

Deciphering cell lineage specification during male sex determination with single-cell RNA sequencing

“…18, 2017;8 2009). Sfrp1 is a secreted negative regulators of the Wnt signaling pathway which have been identified as important for testis descent and normal testicular development (Warr et al, 2009). We also found Pbx1, which have been previously described as expressed in the interstitial compartment of the testis and is required for a normal urogenital differentiation (Schnabel et al, 2003).…”