The role of Hedgehog signalling in pituitary homeostasis in vitro and in vivo

by Dominik Botermann
Doctoral thesis
Date of Examination:2020-10-26
Date of issue:2020-11-03
Advisor:PD Dr. Anja Uhmann
Referee:PD Dr. Anja Uhmann
Referee:Prof. Dr. Hubertus Jarry
Referee:Prof. Dr. Sigrid Hoyer-Fender
Referee:Prof. Dr. Wolfgang Brück
Referee:Dr. Nico Posnien
Referee:Prof. Dr. Peter Burfeind
Persistent Address: http://dx.doi.org/10.53846/goediss-8285

 

 

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Abstract

English

The pivotal role of the Hedgehog (Hh) signalling pathway during embryonal development of the pituitary gland is well established. However, the knowledge about its function in the adult pituitary is still sparse. Our group recently showed that excessive Hh signalling in murine pituitary explants (e.g. by inducible global homozygous Ptch depletion) leads to enhanced growth hormone (Gh), prolactin (Prl), and adrenocorticotropic hormone (Acth) production and enhanced proliferation of Sox2+/Sox9+ pituitary cells, which are assumed to be involved in pituitary homeostasis. Moreover, these studies also revealed that Sox2+ cells of the anterior pituitary express Gli1, a surrogate marker for active Hh signalling. This demonstrated that the Hh signalling pathway plays a role in the homeostasis and hormone production/release of the adult pituitary gland. Moreover, since active Hh signalling is known to be involved in formation/maintenance of a variety of tumour entities the fact that also ACTH-, PRL-, and GH-producing pituitary adenoma show high Hh signalling activity indicated a role of this pathway in pituitary tumorigenesis. However, the pituitary cell type/s which depend on Hh signalling and the regulatory mechanisms were unknown. Thus, in this thesis the effect of a deregulated Hh signalling in Acth-expressing cells of the adult gland was investigated by in vivo approaches. For this purpose, the Hh signalling pathway was activated or inactivated in pro-opiomelanocortin (Pomc)-expressing cells of adult murine pituitary glands by homozygous Ptch or Smo depletion using cell-specific inducible Cre/loxP system. These analyses revealed that neither activation nor inhibition of the Hh signalling pathway impact the function of Pomc+ cells during the development nor in the adult gland. Indeed, tissue expression analyses and in vivo lineage tracing approaches verified that Pomc+ cells never express Gli1 or descent from Gli1+ cells whereas subpopulations of Gh+ cells and folliculostellate cells (FSC) do. To analyse the role of Hh signalling in Gh-producing cells in more detail a new deleter mouse strain was generated. Additionally, in vitro media transfer experiments and transcriptome analyses were conducted to investigate the role of Hh signalling in FSC, which are known to regulate the activity of endocrine pituitary cells, express Sox2 and harbour stem cell-like characteristics. These approaches revealed that Hh signalling activation in FSC leads to the secretion of vasoactive intestinal peptide from FSC and Gh release from GH3 cells indicating that Hh signalling in FSC regulates hormone secretion of endocrine cells in a paracrine manner.
Keywords: Pituitary; Hedgehog; Vasoactive intestinal peptide; Folliculostellate cells
 
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