Notch signaling-mediated cell-to-cell interaction is dependent on E-cadherin adhesion in adult rat anterior pituitary

Abstract

The rat anterior pituitary is composed of hormone-producing cells, non-hormone-producing cells (referred to as folliculostellate cells) and marginal layer cells. In the adult rat, progenitor cells of hormone-producing cells have recently been reported to be maintained within this non-hormone-producing cell population. In tissue, non-hormone-producing cells construct homophilic cell aggregates by the differential expression of the cell adhesion molecule E-cadherin. We have previously shown that Notch signaling, a known regulator of progenitor cells in a number of organs, is activated in the cell aggregates. We now investigate the relationship between Notch signaling and E-cadherin-mediated cell adhesion in the pituitary gland. Immunohistochemically, Notch signaling receptor Notch2 and the ligand Jagged1 were localized within E-cadherin-positive cells in the marginal cell layer and in the main part of the anterior lobe, whereas Notch1 was localized in E-cadherin-positive and -negative cells. Activation of Notch signaling within E-cadherin-positive cells was confirmed by immunostaining of the Notch target HES1. Notch2 and Jagged1 were always co-localized within the same cells suggesting that homologous cells have reciprocal effects in activating Notch signaling. When the E-cadherin function was inhibited by exposure to a monoclonal antibody (DECMA-1) in primary monolayer cell culture, the percentage of HES1-positive cells among Notch2-positive cells was less than half that of the control. The present results suggest that E-cadherin-mediated cell attachment is necessary for the activation of Notch signaling in the anterior pituitary gland but not for the expression of the Notch2 molecule.

N3ICD with the transmembrane domain can effectively inhibit EMT by correcting the position of tight/adherens junctions

“…And then, we have found the direct interaction between the transmembrane full length Notch3 and E-ca according to the result of Co-IP, which will help disassembled E-ca to relocate to cell membrane. In line with our findings, Kikuchi, et al reported that Notch2 and the ligand Jagged1 were localized within E-cadherin-positive cells in the marginal layer cells [50]. In addition, TD +N3ICD overexpression could amplify the roles of Notch3 signaling pathway when compared with N3ICD overexpression alone.…”

Pituitary stem cell regulation: who is pulling the strings?

“…Additional identification of the ligand-exposing cells may further portray the pituitary stem cell niche(s). Remarkably, a recent study showed co-expression of NOTCH2 and JAG1 in the same pituitary stem cells (Batchuluun et al 2017) which is not in line with the model of lateral inhibition. Moreover, in pituitary stem cell-activated conditions of neonatal maturation and somatotrope ablation injury (GH-Cre/ iDTR model), expression of the ligands Jag1 and/or Dll1 was found upregulated in the isolated stem cell populations , Willems et al 2016 ( Table 1), suggesting that NOTCH activation is unfolding between the cells of the stem cell compartment in these activated states.…”

“…In other tissues, GHRL2 has been found to induce the expression of Cdh1 (encoding E-cadherin) (Werth et al 2010, which may explain their colocalization in pituitary stem cells. In return, E-cadherin is also needed for proper NOTCH signaling as inhibition of E-cadherin function using antibodies decreases the proportion of NOTCH2 + cells with HES1 immunopositivity (Batchuluun et al 2017). Of note, another pathway with NOTCH-like juxtacrine makeup recently described in the pituitary stem cell niche is the ephrin-ephrin receptor system (Vankelecom 2010, Cheung et al 2017.…”

MPDZ promotes DLL4-induced Notch signaling during angiogenesis

“…Interestingly, these proteins are associated with either adherens or tight junctions. Notch receptors are also localized at adherens junctions in several cell types ( Batchuluun et al, 2017 ; Benhra et al, 2011 ; Hatakeyama et al, 2014 ; Sasaki et al, 2007 ). Therefore, clustering ligands and receptors at cellular junctions might increase the rate of physical binding events and subsequent Notch signaling activity.…”