Institute for Regenerative Medicine, Institute for Diabetes Obesity and Metabolism, Epigenetics Program, Department of Cell and Developmental Biology, University of Pennsylvania School of Medicine,1056 BRB II/III, 421 Curie Boulevard, Philadelphia, PA 19104, USA.
Development. 2012 Apr;139(8):1447-56. doi: 10.1242/dev.072892.
Pancreatic β-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 β-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 β-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 β-cell development.
胰腺 β 细胞起源于胚胎胰腺干上皮内的 Ngn3(+)内分泌祖细胞。内分泌细胞的出现需要下调 E-钙黏蛋白，但引发这种情况的关键步骤尚不清楚，但对于最终能够从干细胞高效地产生新的 β 细胞可能非常重要。Grg3（生长抑制基因 3，也称为 Tle3）编码 Groucho/TLE 家族共抑制因子的一个成员，其在各种细胞环境中的功能是通过不同的转录因子募集到靶基因来介导的。Grg 蛋白广泛调节祖细胞向分化细胞类型的进展，但具体的发育机制尚不清楚。我们发现 Grg3 在胰腺中的大多数 β 细胞和一部分其他内分泌细胞类型中表达。Grg3 在短暂表达 Ngn3 后，在 Ngn3(+)内分泌祖细胞后代中高度表达。Grg3 敲除胚胎在 E14.5 时死亡，这与胎盘缺陷有关，因此我们进行了 E12.5 胰腺的外植体培养，以允许内分泌细胞分化。由于早期内分泌祖细胞从干上皮分离的缺陷，Grg3 敲除外植体中所有内分泌细胞类型的分化都急剧减少。我们发现 Grg3 通常会抑制 E-钙黏蛋白基因的表达，从而允许内分泌细胞从干上皮分离，并揭示这种转录共抑制因子如何调节 β 细胞发育的这一关键步骤。
