Persistent Expression of Notch2 Delays Gonadotrope Differentiation

Abstract

Normal pituitary gland development requires coordination between maintenance of progenitor cell pools and selection of progenitors for differentiation. The spatial and temporal expression of Notch2 during pituitary development suggested that it could control progenitor cell differentiation in the pituitary. Consistent with this idea, Notch2 is not expressed in Prop1 mutants, and anterior pituitary progenitors in Prop1 mutants appear to be unable to transition from proliferation to differentiation properly, resulting in anterior lobe failed cell specification and evolving hypoplasia. To test the function of Notch2 directly, we used the alphaGSU subunit promoter to express activated NOTCH2 persistently in pre-gonadotropes and pre-thyrotropes of transgenic mice. At birth, there is a small reduction in the population of fully differentiated thyrotropes and almost no fully differentiated gonadotropes. The temporal and spatial expression of Hey1 suggests that it could be a mediator of this effect. Gonadotropes complete their differentiation program eventually, although expression of LH and FSH is mutually exclusive with NOTCH2 transgene expression. This demonstrates that activated Notch2 is sufficient to delay gonadotrope differentiation, and it supports the hypothesis that Notch2 regulates progenitor cell differentiation in the pituitary gland.

Insm1 controls development of pituitary endocrine cells and requires a SNAG domain for function and for recruitment of histone-modifying factors

“…The Insm1 lacZ mutation arrests differentiation of pituitary endocrine cells in fetal development, but the lethal phenotype of the mutation precludes analysis during postnatal stages. Thus, it is possible that by upregulating Notch signaling, the Insm1 lacZ mutation merely delays differentiation, as described for the Notch2 gain-of-function mutation (Raetzman et al, 2006). Upregulation of the Notch signaling pathway, particularly of Dll1 and Hes1, was also noted in…”

“…In normal development, the Notch2 and Notch3 receptors and Hes1 are expressed in progenitor cells, but are excluded from differentiating endocrine cells (Raetzman et al, 2004). A tight control of Notch signaling is required for pituitary development, and sustained Notch activation in progenitor cells by expression of Notch1/2 intracellular domains disrupts and dramatically delays endocrine differentiation (Raetzman et al, 2006;Zhu et al, 2006). Furthermore, the maintenance of progenitors and formation of melanotropes depend on the Notch target genes Hes1 and Hes5 (Kita et al, 2007;Raetzman et al, 2007).…”

Molecular Physiology of Pituitary Development: Signaling and Transcriptional Networks

“…Notch signaling is active during the early phases of pituitary development as indicated by expression of Dll1, Jag1, Notch2, Notch3, as well as the direct downstream targets Hes1 and Hey1. Their expression becomes downregulated in the perspective anterior pituitary at E13.5 as cells undergo lineage commitment (226,228,330). Pituitary-specific inactivation of Rbp-J, which encodes a central mediator of the Notch signaling, using the transgenic Cre line under the control of Pitx1 regulatory sequences, leads to premature differentiation of progenitor cells as well as a conversion of the Pit1 lineage into corticotrope lineage.…”

“…In the later phases of pituitary development, Notch activity is dramatically attenuated, which is absolutely required for terminal differentiation of distinct cell lineages (228,330). Overexpression of the constitutively active form of Notch1 in Pit1 ϩ cells under the control of Pit1 regulatory information (Pit1-NICD) completely blocks terminal differentiation of all three Pit1 lineages.…”

Signaling and epigenetic regulation of pituitary development

“…Overexpression of the constitutively active form of Notch1 in Pit1 + cells (under the control of Pit1 regulatory information, Pit1-NICD) completely blocks terminal differentiation of all three Pit1 lineages [22]. Consistent with these observations, overexpression of the constitutively active form of Notch2 in thyrotropes and gonadotropes (directed by the aGSU regulatory sequences) leads to defects in thyrotrope and gonadotrope differentiation [30]. Diminished expression of a subset of bHLH transcription factors, including Mash1 and Math3, accounts for some of the defects induced by ectopic Notch activation [22].…”