Abstract
The pituitary is an essential endocrine gland regulating multiple processes. Regeneration of endocrine cells is of therapeutic interest and recent studies are promising, but mechanisms of endocrine cell fate acquisition need to be better characterised. The NOTCH pathway is important during pituitary development. Here, we further characterise its role in the murine pituitary, revealing differential sensitivity within and between lineages. In progenitors, NOTCH activation blocks cell fate acquisition, with time-dependant modulation. In differentiating cells, response to activation is blunted in the POU1F1 lineage, with apparently normal cell fate specification, while POMC cells remain sensitive. Absence of apparent defects in Pou1f1-Cre; Rbpjfl/fl mice further suggests no direct role for NOTCH signalling in POU1F1 cell fate acquisition. In contrast, in the POMC lineage, NICD expression induces a regression towards a progenitor-like state, suggesting that the NOTCH pathway specifically blocks POMC cell differentiation. These results have implications for pituitary development, plasticity and regeneration. Activation of NOTCH signalling in different cell lineages of the embryonic murine pituitary uncovers an unexpected differential sensitivity, and this consequently reveals new aspects of endocrine lineages development and plasticity.
Highlights
The pituitary is an essential endocrine gland that is closely associated with the hypothalamus, in the ventral diencephalon, which controls its hormonal secretions
SOX2 is present in all pituitary progenitors (Fauquier et al, 2008; Rizzoti et al, 2013), while NKX3.1 is expressed predominantly in those located in the dorsal pituitary, peaking at 12.5dpc (Treier et al, 1998) (Goldsmith et al, 2016)
Our experiments reveal an unexpected differential sensitivity to NOTCH Intracellular Domain (NICD) expression between lineages and, in consequence, provide a better understanding of the physiological role of the pathway during pituitary development
Summary
The pituitary is an essential endocrine gland that is closely associated with the hypothalamus, in the ventral diencephalon, which controls its hormonal secretions. Pituitary hormone deficiencies, either congenital (1 in 3500 to 10000 births) (Alatzoglou and Dattani, 2009) or acquired later in life, mostly caused by tumours or brain damage, are associated with significant morbidity. Others, have characterized a population of stem cells (SCs) in the mouse pituitary (Rizzoti et al, 2013) (Andoniadou et al, 2013). The differentiation of embryonic SC to generate endocrine cells has been demonstrated in vitro (Suga et al, 2011). It would be of therapeutic interest to utilize SCs to generate endocrine cells; the limited efficiency of current protocols highlights the requirement for improved characterization of the mechanisms of endocrine cell fate acquisition
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