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 folliculo-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.
Highlights
The pituitary gland is a key regulator of body homeostasis and responsible for signal exchanges between the hypothalamus and peripheral organs
We focused on the two neuropeptides RF(Arg-Phe)amide family 26 amino acid peptide (Qrfp) and vasoactive intestinal peptide (Vip), which are known to regulate pituitary hormone release (Matsushita et al 1981, Chihara et al 1982, Abe et al 1985, Denef et al 1985, Bluet-Pajot et al 1987, Bjoro et al 1990, Alexander & Sander 1994, Mazzocchi et al 1998, Vleck & Patrick 1999, Fazekas et al 2000, Christian et al 2007, Leprince et al 2017) and whose expression levels were significantly elevated in Smoothened Agonist (SAG)-stimulated TtT/GF cells compared to the controls (Fig. 6A, B and D). qRT-PCRbased expression analyses verified the significant increase of Vip expression in SAG-treated TtT/GF cells (Fig. 7A), whereas the absolute Qrfp reads remained under quantitative real-time PCR (qRT-PCR) detection level
These experiments were not conclusive with respect to the Hh-responsive pituitary cell type in the normal gland (Pyczek et al 2016). This information is of great importance because GLI1 and SHH are highly expressed by GH, PRL- and ACTH-expressing human pituitary adenoma, which suggests that HH signaling has an impact on pituitary tumor formation (Pyczek et al 2016)
Summary
The pituitary gland is a key regulator of body homeostasis and responsible for signal exchanges between the hypothalamus and peripheral organs. Besides of the six different endocrine cell types (e.g. corticotrophs/ adrenocorticotropic hormone- (Acth), somatotrophs/ growth hormone- (Gh), prolactin- (Prl), thyroidstimulating hormone-, luteinizing hormone-, folliclestimulating hormone-secreting cells), the anterior lobe (AL) of the pituitary consists of Sox2+ (stem) cells and a meshwork of non-endocrine Sox2+ folliculo-stellate cells (FSC). The latter ones are implicated in regulation and maintenance of the endocrine cells by delivering paracrine factors (reviewed in Cox et al 2017).
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