Loss of the Protein p8 Leads to Delayed LHβ Expression, Delayed Female Sexual Maturation, and Testicular Development of a Sertoli-Cell-Only Syndrome-Like Phenotype.

Abstract

The high mobility group factor p8 plays a role in temporal expression of LHβ during gonadotrope development. At embryonic day (e) 16.5, a time when LHβ is detectable in wild-type (WT) mice, it is not detectable in p8 knockout (p8-KO) mice. Expression of LHβ is initiated by e17.5 in these mice and expression is fully recovered by postnatal day (p) 2. Factors important for gonadotrope differentiation and maturation, Gata2 and αGSU, are not differentially expressed in p8-KO and WT embryos at e17.5; neither is the thyrotrope-specific factor TSHβ. Therefore, the delay in LHβ expression in gonadotropes of p8-KO mice does not appear to result from an overall delay in pituitary development. In addition, the role of p8 in gonadotropin expression appears specific for LHβ, as no significant difference in FSHβ is observed between p8-KO and WT embryos. The importance of p8 in the reproductive axis is not limited to gonadotropes, as the gonads are also impacted by its absence. Ovaries of female p8-KO mice lack corpora lutea (CL) at eight weeks, an age in which CL are present in WT littermates. Sexual maturity, defined by the presence of CL, is recovered by 11 weeks of age in p8-KO mice. Conversely, the testes of p8-KO males appear normal up to eight months of age. By 10 months, however, these mice develop a condition in which a significant number of seminiferous tubules lack germ cells, an abnormality reminiscent of human Sertoli-cell-only syndrome (SCOS). These reproductive phenotypes are likely due to the loss of p8 directly at the ovary and testis, rather than loss of p8 in the gonadotrope, because p8 is undetectable in WT gonadotropes by p2 and remains absent in adulthood. Indeed, quantitative PCR analysis indicates WT adult ovaries and testes express large quantities of p8 mRNA. Identification of gonadal cell types that express p8 will be critical to investigating how the loss of p8 results in delayed female sexual maturation and testicular development of SCOS. This research is supported by a Research Starter Grant from the PhRMA Foundation (CCQ) and a Predoctoral Fellowship from the American Heart Association (CMP).