ESPE Yearbook of Paediatric Endocrinology

Proc Natl Acad Sci USA 121(40) (2024) e241026912.PMID: 39320918

Brief Summary: The architecture and function of the anterior pituitary rely on precise cell-cell communication within interdigitated hormone-secreting networks. However, the specific signals orchestrating these interactions remained unknown. This experimental study identifies that corticotrope-derived factors, particularly the secreted FGF1, play a pivotal paracrine function in sustaining pituitary structure and growth.

This study from Drouin’s laboratory uses elegant murine genetics tools combined with single-cell transcriptomic analyses and functional validation in vitro and in vivo to identify a novel role of secreted FGF1 from corticotropes. The authors identify that mouse knock-out of Tpit (a corticotrope-specific transcription factor) leads to marked pituitary hypoplasia and diminished somatotrope cell numbers causing systemic growth defect. Single-cell RNA-seq revealed that FGF1 expression in corticotropes is Tpit-dependent and this is further demonstrated using ATAC and CHIP-seq. Moreover, loss of Fgf1 recapitulated the phenotypes observed in Tpit deficiency. Fgf1 knockout mice exhibit reduced pituitary size, somatotrope hypoplasia, disrupted cell polarity, and stunted growth, mirroring Tpit-KO phenotypes. Together, these results compellingly position FGF1 as a corticotrope-secreted paracrine morphogen essential for proper pituitary architecture and growth.

As with all great papers, there are some open questions for this work. While loss of FGF1 mirrors loss of Tpit, the reverse approach (rescue experiments by exogenous FGF1 in Tpit-KO) would greatly strengthen causality. Although mouse data are compelling, translational relevance to human pituitary development or disease will require further experiments. Interestingly mutations in Fgf8 have been identified in patients with congenital hypopituitarism’s (CH) indicating the role of this pathway in pituitary hormone deficiencies in humans. Hence, further investigation to identify if mutations in FGF1 or its receptors are cause of CH in humans are warranted. Overall, this study sets the stage for a richer understanding of paracrine-driven organogenesis in complex endocrine systems.