The role of Hedgehog signaling in the adult pituitary gland and the formation of pituitary adenoma

• Applicant: Privatdozentin Dr. Anja Uhmann
• Subject Area: Endocrinology, Diabetology, Metabolism ; Hematology, Oncology ; Molecular and Cellular Neurology and Neuropathology
• Term: from 2016 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 326969103

The Hedgehog (Hh) signaling pathway plays an important role in homeostasis and pathology of adult organs. However, the function of the pathway in maintenance and pathology of the adult pituitary is largely unknown. To this end we analyzed in a previous study the impact of a ubiquitous activation of the signaling pathway in the murine adult pituitary, which causes an increased proliferation of Sox2+ pituitary cells as well as an increased expression of hormones of the anterior lobe (Acth, adrenocorticotropic hormone; Gh, growth hormone; Prl, prolactin). In addition, ACTH-, GH- and PRL-expressing human pituitary adenomas show significantly higher activation of the Hh signaling cascade compared to other subtypes, indicating a role of Hh signaling in homeostasis and pathology of the adult pituitary. Our data of first funding period now show that neither Acth- nor Prl-expressing cells are derived from Gli1+ cells (i.e. cells with active Hh signaling). Even an in vivo deregulation of Hh signaling in Pomc- (or Acth-) expressing cells has no effect on the functionality of these cells, neither during organogenesis nor in the adult organ. However, somatotropic cells and Sox2-expressing folliculostellate cells (FSC) are derived from Gli1+ cells of the adult pituitary. Since FSC regulate hormone secretion by endocrine cells and control the microcirculation of ions, nutrients and waste products, these data suggest that Hh signaling is involved in intercellular communication and paracrine exchange of FSC with endocrine cells. This could be true for the healthy gland as well as for pituitary adenomas, since the tumor micro environment of up to 69% of these tumors contains FSC in direct contact with tumor cells. Indeed, we furthermore demonstrated that active Hh signaling is involved in FSC-mediated regulation of Gh production/release in vitro. Moreover, our data show that Hh-stimulated FSC secrete the neuropeptide Vasoactive intestinal peptide (Vip) which induces hormone secretion from somatotrophs. To elucidate the role of Hh signaling somatotrophs and FSC of the adult pituitary and to furthermore investigate whether the Vip-mediated hormone release also applies to the in vivo situation and possibly plays a role in pituitary pathology, we will analyse human pituitary and tumor samples and investigate the effects of a deregulated Hh signaling cascade in somatotrophs and/or FSC in transgenic mouse models. If our results should support our hypothesis, it might open new possibilities for novel targeted therapies against hormone-producing adenoma and associated diseases (e.g. Morbus Cushing, acromegaly and hyperprolactinemia).

• DFG Programme: Research Grants