Oliver-Krasinski Jennifer M, Kasner Margaret T, Yang Juxiang, Crutchlow Michael F, Rustgi Anil K, Kaestner Klaus H, Stoffers Doris A
Institute for Diabetes, Obesity and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
J Clin Invest. 2009 Jul;119(7):1888-98. doi: 10.1172/JCI37028.
Heterozygous mutations in the gene encoding the pancreatic homeodomain transcription factor pancreatic duodenal homeobox 1 (PDX1) are associated with maturity onset diabetes of the young, type 4 (MODY4) and type 2 diabetes. Pdx1 governs the early embryonic development of the pancreas and the later differentiation of the insulin-producing islet beta cells of the endocrine compartment. We derived a Pdx1 hypomorphic allele that reveals a role for Pdx1 in the specification of endocrine progenitors. Mice homozygous for this allele displayed a selective reduction in endocrine lineages associated with decreased numbers of endocrine progenitors and a marked reduction in levels of mRNA encoding the proendocrine transcription factor neurogenin 3 (Ngn3). During development, Pdx1 occupies an evolutionarily conserved enhancer region of Ngn3 and interacts with the transcription factor one cut homeobox 1 (Hnf6) to activate this enhancer. Furthermore, mRNA levels of all 4 members of the transcription factor network that regulates Ngn3 expression, SRY-box containing gene 9 (Sox9), Hnf6, Hnf1b, and forkhead box A2 (Foxa2), were decreased in homozygous mice. Pdx1 also occupied regulatory sequences in Foxa2 and Hnf1b. Thus, Pdx1 contributes to specification of endocrine progenitors both by regulating expression of Ngn3 directly and by participating in a cross-regulatory transcription factor network during early pancreas development. These results provide insights that may be applicable to beta cell replacement strategies involving the guided differentiation of ES cells or other progenitor cell types into the beta cell lineage, and they suggest a molecular mechanism whereby human PDX1 mutations cause diabetes.
编码胰腺同源异型结构域转录因子胰腺十二指肠同源盒1（PDX1）的基因中的杂合突变与青年发病的成年型糖尿病4型（MODY4）和2型糖尿病相关。Pdx1调控胰腺的早期胚胎发育以及内分泌区产生胰岛素的胰岛β细胞的后期分化。我们获得了一个Pdx1低表达等位基因，该基因揭示了Pdx1在内分泌祖细胞特化中的作用。该等位基因的纯合小鼠在内分泌谱系中出现选择性减少，这与内分泌祖细胞数量减少以及编码前内分泌转录因子神经生成素3（Ngn3）的mRNA水平显著降低有关。在发育过程中，Pdx1占据Ngn3的一个进化保守增强子区域，并与转录因子单切口同源盒1（Hnf6）相互作用以激活该增强子。此外，在纯合小鼠中，调节Ngn3表达的转录因子网络的所有4个成员，即含SRY盒基因9（Sox9）、Hnf6、Hnf1b和叉头框A2（Foxa2）的mRNA水平均降低。Pdx1还占据Foxa2和Hnf1b中的调控序列。因此，Pdx1通过直接调节Ngn3的表达以及在胰腺早期发育过程中参与交叉调节转录因子网络，有助于内分泌祖细胞的特化。这些结果为涉及将胚胎干细胞或其他祖细胞类型定向分化为β细胞谱系的β细胞替代策略提供了可能适用的见解，并提示了一种人类PDX1突变导致糖尿病的分子机制。
