SFEBES2022 Oral Communications Reproductive and Neuroendocrinology (6 abstracts)
BRF1-mediated paracrine signalling from pituitary stem cells is required for terminal differentiation of pituitary committed progenitors
Thea L Willis 1 , Saba Manshaei 2 , Virinder Reen 3 , Husayn Pallikonda 3 , Jodie Birch 3 , Val Yianni 1 , Emily J Lodge 1 , Dominic Withers 3 , Jesus Gil 3 , Juan Pedro Martinez-Barbera 2 & Cynthia L Andoniadou 1
1King’s College London, London, United Kingdom; 2University College London, London, United Kingdom; 3Imperial College London, London, United Kingdom
The pituitary gland is a critical endocrine organ regulating multiple essential physiological processes including growth, reproduction, metabolism and the stress response. Hormone-producing pituitary cell lineages are derived from a population of embryonic precursors expressing the transcription factor SOX2. These cells maintain multipotency into early postnatal life, acting as the resident population of pituitary stem cells (PSCs) and contributing to all the endocrine cell lineages. In addition to this direct contribution to pituitary turnover, paracrine signalling from PSCs is necessary for cell proliferation of neighbouring progenitors. It is not known if SOX2+ PSCs are involved in other aspects of neighbouring cell regulation during normal physiology. Utilising scRNA-sequencing of SOX2+ PSCs from Sox2Egfp/+ mouse pituitaries at three postnatal stages from P3 to P56, we show that the SOX2+ PSC population consists of three subgroups (SC1, SC2 and SC3). We reveal that SC1-SC2 express abundant cytokines and secreted factors, suggesting a paracrine function. In contrast SC3, characterised by robust expression of Lef1, is a committing PSC cluster and its presence diminishes with age. We unearth differential and conserved markers of PSC clusters and identify RNA binding factor BRF1 as conserved in one subgroup at all ages. We show that BRF1 is highly expressed in PSCs and that its dysregulation in embryonic pituitary cells results in severe hypopituitarism due to a failure of two distinct lineage-committed progenitors to terminally differentiate into hormone-producing cells. Additionally, there is a significant reduction of the stem cell compartment. The differentiation failure can be rescued in vivo, in mutant pituitaries where activation of constitutively active BRF1 is restricted to few SOX2+ PSCs in a mosaic manner. Together, these data indicate the presence of functionally distinct groups of SOX2+ pituitary stem cells and reveal a critical role for PSCs in driving terminal differentiation of endocrine cells.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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