White Peter, May Catherine Lee, Lamounier Rodrigo N, Brestelli John E, Kaestner Klaus H
University of Pennsylvania, Medical School, Department of Genetics, Institute for Diabetes, Obesity and Metabolism, 415 Curie Blvd., Philadelphia, PA 19104, USA.
Diabetes. 2008 Mar;57(3):654-68. doi: 10.2337/db07-1362. Epub 2007 Dec 10.
The global incidence of diabetes continues to increase. Cell replacement therapy and islet transplantation offer hope, especially for severely affected patients. Efforts to differentiate insulin-producing beta-cells from progenitor or stem cells require knowledge of the transcriptional programs that regulate the development of the endocrine pancreas.
Differentiation toward the endocrine lineage is dependent on the transcription factor Neurogenin 3 (Neurog3, Ngn3). We utilize a Neurog3-enhanced green fluorescent protein knock-in mouse model to isolate endocrine progenitor cells from embryonic pancreata (embryonic day [E]13.5 through E17.5). Using advanced genomic approaches, we generate a comprehensive gene expression profile of these progenitors and their immediate descendants.
A total of 1,029 genes were identified as being temporally regulated in the endocrine lineage during fetal development, 237 of which are transcriptional regulators. Through pathway analysis, we have modeled regulatory networks involving these proteins that highlight the complex transcriptional hierarchy governing endocrine differentiation.
We have been able to accurately capture the gene expression profile of the pancreatic endocrine progenitors and their descendants. The list of temporally regulated genes identified in fetal endocrine precursors and their immediate descendants provides a novel and important resource for developmental biologists and diabetes researchers alike.
全球糖尿病发病率持续上升。细胞替代疗法和胰岛移植带来了希望，尤其是对于重症患者。从祖细胞或干细胞分化产生胰岛素分泌β细胞的研究需要了解调节内分泌胰腺发育的转录程序。
向内分泌谱系的分化依赖于转录因子神经生成素3（Neurog3，Ngn3）。我们利用Neurog3增强型绿色荧光蛋白敲入小鼠模型从胚胎胰腺（胚胎第[E]13.5天至E17.5天）中分离内分泌祖细胞。使用先进的基因组学方法，我们生成了这些祖细胞及其直接后代的全面基因表达谱。
共鉴定出1029个在胎儿发育期间内分泌谱系中受到时间调控的基因，其中237个是转录调节因子。通过通路分析，我们构建了涉及这些蛋白质的调控网络模型，突出了控制内分泌分化的复杂转录层次结构。
我们能够准确捕捉胰腺内分泌祖细胞及其后代的基因表达谱。在胎儿内分泌前体及其直接后代中鉴定出的受时间调控的基因列表为发育生物学家和糖尿病研究人员提供了一个新颖且重要的资源。
