The transcriptional co-repressor Grg3/Tle3 promotes pancreatic endocrine progenitor delamination and β-cell differentiation

Abstract

SUMMARYPancreatic -cells arise from Ngn3 + endocrine progenitors within the trunk epithelium of the embryonic pancreas. The emergence of endocrine cells requires E-cadherin downregulation, but the crucial steps that elicit such are not clear, yet probably important for ultimately being able to efficiently generate -cells de novo from stem cells. Grg3 (groucho-related gene 3, also known as Tle3), encodes a member of the Groucho/TLE family of co-repressors and its function in various cell contexts is mediated by recruitment to target genes by different transcription factors. Grg proteins broadly regulate the progression of progenitor cells to differentiated cell types, but specific developmental mechanisms have not been clear. We find that Grg3 is expressed in most -cells and a subset of other endocrine cell types in the pancreas. Grg3 is highly expressed in Ngn3 + endocrine progenitor descendants just after transient Ngn3 expression. Grg3-null embryos die at E14.5, which is associated with placental defects, so we explanted E12.5 pancreata to allow endocrine differentiation to occur in culture. Grg3 knockout explants displayed a drastic decrease in the differentiation of all endocrine cell types owing to defects in the delamination of early endocrine progenitors from the trunk epithelium. We find that Grg3 normally suppresses E-cadherin gene expression, thereby allowing delamination of endocrine cells from the trunk epithelium and revealing how this transcriptional co-repressor modulates this crucial step of -cell development.

Feedback control of growth, differentiation, and morphogenesis of pancreatic endocrine progenitors in an epithelial plexus niche

“…Consistent with a proposed model for lateral Notch pathway activation by Ngn3-producing cells (Metzger et al 2012;Shih et al 2012;Qu et al 2013), genetic ablation of Ngn3, as reported previously (Magenheim et al 2011a), caused loss of Hes1 (a Notch transcriptional effector) signal in Sox9 + epithelial cells, suggesting that Notch pathway activity is Ngn3-dependent and is engaged locally in the plexus state (Supplemental Fig. 9A-D).…”

The Groucho/Transducin‐like enhancer of split protein family in animal development

“…Using embryos lacking Tle3 , it was demonstrated that TLE3 is required for proper differentiation of endocrine cell types in the pancreas by downregulating the expression of the cell adhesion molecule E‐cadherin, a necessary step for delamination of the pancreatic endocrine cells . This study also suggests that TLE3 might be important for pancreatic endocrine cell, especially β‐cell, maturation, and homeostasis . Recent data suggest that TLE3 in mice, and TLE1 in humans, are crucial for maintaining the monohormonal identity of β‐cells .…”

Dynamics of genomic H 3 K 27me3 domains and role of EZH 2 during pancreatic endocrine specification

“…For half‐embryo cultures, E8.25 (2–7 somite pair) embryos were dissected, the posterior half was removed from the first somite site, and the anterior half was cultured at 37°C for 48 h in Dulbecco's modified Eagle's medium (DMEM) containing 10% calf serum (Hyclone) (Wandzioch & Zaret, ). For pancreas explant cultures, E14.5 pancreata were dissected and cultured on Nuclepore Track‐Etch Membranes (Whatman, 110414) floating on DMEM containing 10% FBS for 4 days (Metzger et al , ).…”