ESPE Yearbook of Paediatric Endocrinology

Nat Commun 16, 4280 (2025). PMID: 40399281

Brief Summary: This experimental study presents compelling evidence that murine postnatal gonadotrophs have a dual origin. Traditionally thought to arise from embryonic stem cells, this research now demonstrates that the majority of adult gonadotrophs derive from postnatal Sox2⁺ pituitary stem cells, particularly during early life and up to puberty. Surprisingly, this second wave of differentiation occurs independently of gonadal hormones and GnRH signalling, suggesting an intrinsic, stem cell-driven expansion mechanism to establish reproductive capacity.This study used sophisticated cell lineage tracing combined with single cell transcriptomic analyses to show that pituitary gonadotrophs (that produce LH and FSH) are derived mainly postnatally from Sox2+ve Sox9+ve pituitary resident stem cells. The authors generate a novel genetic lineage tracing murine line, Sox2rtTA (activated with doxycycline, that avoids tamoxifen effects on hypothalamic-pituitary-gonadal axis), allowing precise temporal labelling of Sox2C stem cells (Sox2rtTA;RosaYFP) during postnatal time windows. Cell lineage tracing shows that some gonadotrophs are produced embryonically form embryonic Sox2Cve stem cells but these represent only a minority of the adult LH-FSH adult gonadotrophs as the majority are produced postnatally during a winddown time of mini-puberty. Importantly, the authors show that gonadotroph production is independent of GnRH or the feedback loops from gonads since ablation of these signals still results in gonadotroph differentiation. Single-cell transcriptomics and imaging: UMAP and pseudotime revealed a clear trajectory from Sox2 stem cells toward gonadotroph identity. Hence, this second wave of differentiation occurs independently of gonadal hormones and GnRH signalling, suggesting yet unknown intrinsic signal that triggers stem cell-driven expansion mechanism to establish reproductive capacity.

The findings are important in pituitary research field in several aspects as it identifies 2 temporally distinct populations of cell fate regulation. This may underlie functional or regulatory differences among gonadotroph subtypes (embryonic versus postnatal origin), which are yet unknown. Given that most gonadotrophs form postnatally, this window could be a vulnerability point. The authors propose that disorders like congenital hypogonadotropic hypogonadism (CHH) might distinctly affect embryonic vs. postnatal lineages, a hypothesis that needs to be tested in future studies. Importantly, since the authors show that the stem cell that will give rise to the majority of gonadotrophs arise independently of GnRH/gonadal signals, there’s the exciting prospect of harnessing endogenous signals to restore gonadotroph function, for example, in hypogonadism or pituitary injury.

Although GnRH/gonadal independence is shown, what upstream signals drive stem cell differentiation is not known. This study leaves open the mechanistic question of niche cues or systemic factors involved in triggering this second gonadotroph wave. Moreover, confirming whether human pituitary has a similar dual origin architecture is essential, especially for designing regenerative strategies.