Hedgehog signaling in endocrine and folliculo-stellate cells of the adult pituitary

Abstract

Ubiquitous overactivation of Hedgehog signaling in adult pituitaries results in increased expression of proopiomelanocortin (Pomc), growth hormone (Gh) and prolactin (Prl), elevated adrenocorticotropic hormone (Acth) production and proliferation of Sox2+ cells. Moreover, ACTH, GH and PRL-expressing human pituitary adenomas strongly express the Hedgehog target GLI1. Accordingly, Hedgehog signaling seems to play an important role in pathology and probably also in homeostasis of the adult hypophysis. However, the specific Hedgehog-responsive pituitary cell type has not yet been identified. We here investigated the Hedgehog pathway activation status and the effects of deregulated Hedgehog signaling cell-specifically in endocrine and non-endocrine pituitary cells. We demonstrate that Hedgehog signaling is unimportant for the homeostasis of corticotrophs, whereas it is active in subpopulations of somatotrophs and follicullo-stellate cells in vivo. Reinforcement of Hedgehog signaling activity in folliculo-stellate cells stimulates growth hormone production/release from somatotrophs in a paracrine manner, which most likely is mediated by the neuropeptide vasoactive intestinal peptide. Overall, our data show that Hedgehog signaling affects the homeostasis of pituitary hormone production via folliculo-stellate cell-mediated regulation of growth hormone production/secretion.

Morphometric analysis of somatotropic and folliculostellate cells of human anterior pituitary during ageing

“…Analysis of the correlation between morphometric parameters of GH and FS cells indicated the presence of a statistically significant negative correlation between the average volume density of anterior pituitary FS cells and the nuclear-cytoplasmic ratio of GH cells, suggesting that homeostasis of the growth hormone production/secretion exists [22].…”

Histopathological Characteristics of Folliculo-stellate Cells in Pituitary Glands of Wild Type, Obese and High-fat Diet Induced Mice

“…It is now known that in vitro the Hedgehog signaling pathway leads FSC to stimulate the production and release of GH by the anterior pituitary, but the production of CXCL12 by FSC can have the same effect [23,24] . By establishing a communication network between the FSC and with the hormone-producing cells, this may correspond in vivo to a physiological reaction mechanism to the increased intake of fatty acids, evident in HFD mice, influencing the expression of FSC [25,26] .…”

The hidden hedgehog of the pituitary: hedgehog signaling in development, adulthood and disease of the hypothalamic-pituitary axis

“…Compared to these studies, our data rather hint towards an indirect hormone regulation by HH signaling in the adult adenohypophysis. We found that HH signaling activation in murine pituitary explants induces Acth , Gh , Prl and Cga expression ( 11 ), whereas a corticotroph-specific Ptch1 or Smo depletion in vivo does not ( 12 ). Moreover, neither corticotrophs nor lactotrophs show active HH signaling in adult mice ( 12 ).…”

“…We found that HH signaling activation in murine pituitary explants induces Acth , Gh , Prl and Cga expression ( 11 ), whereas a corticotroph-specific Ptch1 or Smo depletion in vivo does not ( 12 ). Moreover, neither corticotrophs nor lactotrophs show active HH signaling in adult mice ( 12 ). Interestingly, the FS cell line TtT/GF is responsive to HH signaling activation.…”

“…This contrasts the data from human adenohypophysis samples that show no PTCH1 expression in corticotrophs and no GLI1 and PTCH2 expression in lactotrophs/somatotrophs ( 11 , 13 , 14 ). In addition, lineage-tracing experiments showed that approximately 2/3 of all somatotrophs and 2/3 of all FS cells descend from GLI1-expressing cells in the murine adenohypophysis ( 12 ), indicating a role of HH signaling in somatotrophs and FS cells. Together, these data are somewhat inconclusive.…”