Jenny Marjorie, Uhl Céline, Roche Colette, Duluc Isabelle, Guillermin Valérie, Guillemot Francois, Jensen Jan, Kedinger Michèle, Gradwohl Gérard
INSERM U381, 3 avenue Molière, 67200, Strasbourg, France.
EMBO J. 2002 Dec 2;21(23):6338-47. doi: 10.1093/emboj/cdf649.
Endocrine cells of the pancreas and the gastrointestinal tract derive from multipotent endodermal stem cells. We have shown previously that the basic helix- loop-helix (bHLH) transcription factor neurogenin3 (ngn3) is required for the specification of the endocrine lineage in uncommitted progenitors in the developing pancreas. We investigate herein the expression and the function of ngn3 in the control of endocrine cell development in the intestinal and gastric epithelium. Our results indicate that as in the pancreas, gastrointestinal endocrine cells derive from ngn3-expressing progenitors. Mice homozygous for a null mutation in ngn3 fail to generate any intestinal endocrine cells, and endocrine progenitor cells are lacking. The other main intestinal epithelial cell types differentiate properly. In contrast, in the glandular stomach, the differentiation of the gastrin- (G cells) and somatostatin (D cells)-secreting cells is impaired whereas serotonin- (enterochromaffin EC cells), histamine- (enterochromaffin-like ECL cells) and ghrelin (X/A cells)-expressing cells are still present. Thus, ngn3 is strictly required for endocrine cell fate specification in multipotent intestinal progenitor cells, whereas gastric endocrine development is both ngn3 dependent and independent.
胰腺和胃肠道的内分泌细胞起源于多能内胚层干细胞。我们先前已经表明，碱性螺旋-环-螺旋（bHLH）转录因子神经生成素3（ngn3）是发育中的胰腺中未分化祖细胞内分泌谱系特化所必需的。我们在此研究ngn3在肠道和胃上皮内分泌细胞发育调控中的表达和功能。我们的结果表明，与胰腺一样，胃肠道内分泌细胞起源于表达ngn3的祖细胞。ngn3基因纯合无效突变的小鼠无法产生任何肠道内分泌细胞，且缺乏内分泌祖细胞。其他主要的肠道上皮细胞类型分化正常。相比之下，在腺胃中，分泌胃泌素的细胞（G细胞）和分泌生长抑素的细胞（D细胞）的分化受损，而表达5-羟色胺的细胞（肠嗜铬EC细胞）、表达组胺的细胞（类肠嗜铬ECL细胞）和表达胃饥饿素的细胞（X/A细胞）仍然存在。因此，ngn3是多能肠道祖细胞内分泌细胞命运特化所严格必需的，而胃内分泌发育既依赖ngn3也不依赖ngn3。
