Notch Signaling in Postnatal Pituitary Expansion: Proliferation, Progenitors, and Cell Specification

Abstract

Mutations in PROP1 account for up to half of the cases of combined pituitary hormone deficiency that result from known causes. Despite this, few signaling molecules and pathways that influence PROP1 expression have been identified. Notch signaling has been linked to Prop1 expression, but the developmental periods during which Notch signaling influences Prop1 and overall pituitary development remain unclear. To test the requirement for Notch signaling in establishing the normal pituitary hormone milieu, we generated mice with early embryonic conditional loss of Notch2 (conditional knockout) and examined the consequences of chemical Notch inhibition during early postnatal pituitary maturation. We show that loss of Notch2 has little influence on early embryonic pituitary proliferation but is crucial for postnatal progenitor maintenance and proliferation. In addition, we show that Notch signaling is necessary embryonically and postnatally for Prop1 expression and robust Pit1 lineage hormone cell expansion, as well as repression of the corticotrope lineage. Taken together, our studies identify temporal and cell type-specific roles for Notch signaling and highlight the importance of this pathway throughout pituitary development.

Multi‐genic pattern found in rare type of hypopituitarism: a whole‐exome sequencing study of Han Chinese with pituitary stalk interruption syndrome

“…Among these mutated genes, transcriptional factor HESX1 ‐mediated repression of Wnt/β‐catenin targets is required for the normal development of anterior forebrain 24; Wnt/β‐catenin signalling promotes midbrain dopaminergic progenitor specification, proliferation and neurogenesis by up‐regulating OTX2 in progenitors 25; Notch signalling has been linked to PROP1 expression 26; GPR161 and CDON , the latest mutations found in patients with PSIS by WES recently, are regulators of Shh pathway 27, 28. Collectively, these pathways seem to be critical to pituitary development.…”

Pituitary stem cell regulation: who is pulling the strings?

“…These and other markers (including E-cadherin, glial cell line derived neurotrophic factor family receptor alpha 2 or GFRA2, nestin and PROP1) were found in the cells of the marginal zone bordering the cleft (Fauquier et al 2008, Gleiberman et al 2008, GarciaLavandeira et al 2009, Yoshida et al 2011, with a similar expression and organization picture in human pituitary (Garcia-Lavandeira et al 2009. In addition, SOX2 + cells were also found within the gland's parenchyma, mostly occurring in clusters and also expressing SOX9 and E-cadherin (Fauquier et al 2008, Chen et al 2013, Nantie et al 2014, Zhu et al 2015. The marginal zone and parenchymal clusters are proposed to represent plural stem cell niches in the pituitary to enable swift adaptation during (subtle) cell remodeling processes (Vankelecom 2012, Vankelecom & Chen 2014.…”

“…Also in the pituitary, NOTCH activity in the embryonic progenitor cells is essential for maintenance of the undifferentiated state (Zhu et al 2006, Nantie et al 2014, with HES1 inhibiting progression toward hormonal cells (Zhu et al 2006). In analogy, enforced persistent activation of NOTCH signaling in the more committed cells obstructs their final differentiation during embryogenesis (Zhu et al 2006, Figure 1 Overview of the signaling pathways potentially involved in pituitary stem cell regulation.…”

“…1A and Table 1). Interestingly, the same NOTCH receptor subtypes are expressed in the embryonic pituitary progenitor cells, particularly around the cleft (Raetzman et al 2004, Zhu et al 2006, and Notch2 remains predominantly expressed around the cleft in the postnatal pituitary (Nantie et al 2014). It is not known yet how NOTCH2 and NOTCH3 functionally overlap in the pituitary.…”

“…In Prop1-mutant mice exhibiting a dwarf phenotype (Prop1 df/df ), expression of NOTCH2 protein is absent, while Notch3 gene expression is not affected (Raetzman et al 2004), positioning NOTCH2 but not NOTCH3 downstream of PROP1. Mice with Cre-mediated conditional knockout of Notch2 under the control of Foxg1, a factor expressed in RP cells at E9.5 , showed no obvious defects during pituitary embryonic development, suggesting that other NOTCH receptors like NOTCH3 may take over or provide sufficient NOTCH signaling during embryogenesis (Nantie et al 2014). However, the Notch2 mutants showed a reduction in postnatal AP volume, together with a decrease in PIT1 lineage (in particular, GH + and TSHβ + ) cells and an increase in POMC + cells.…”