Lack of TCF2/vHNF1 in mice leads to pancreas agenesis
Lack of TCF2/vHNF1 in mice leads to pancreas agenesis
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DOI：
10.1073/pnas.0405776102
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发表时间：
2005-02-01
影响因子：
11.1
通讯作者：
Cereghini, S
中科院分区：
文献类型：
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作者：
Haumaitre, C;Barbacci, E;Cereghini, S
人类POLI - 同源框TCF2（vHNF1，HNF1β）基因的杂合突变与青少年发病的成人型糖尿病5型以及泌尿生殖道发育异常有关。最近，有报道称在几名青少年发病的成人型糖尿病5型患者中出现胰腺萎缩，这表明TCF2不仅对成人胰腺功能是必需的，而且对其正常发育也是必需的。Tcf2缺陷型小鼠由于内脏内胚层形成缺陷在原肠胚形成之前死亡。为了研究该因子在胰腺发育中的作用，我们通过四倍体聚合挽救了这种早期致死性。我们表明TCF2在胰腺发育的最初阶段具有重要功能，这与其从最早阶段就划定整个胰腺芽的表达区域相关。缺乏TCF2会导致在胚胎第13.5天胰腺发育不全。在更早的阶段，只有一个背侧芽原基短暂形成，并表达转录因子Ipf1和HIxb9，但缺乏参与获得胰腺命运的关键转录因子Ptf1a以及所有内分泌前体细胞。在Tcf2（-/-）胚胎中，肠道的区域特化也受到干扰，表现为Shh的异位表达以及在胃后部和十二指肠中缺乏Ihh和Ipf1。我们的研究结果强调了Tcf2对于确保胃 - 十二指肠上皮中关键调节分子的准确表达以及胰腺命运的正确获得的必要性。这项研究为控制胰腺发育的早期分子事件提供了进一步的见解，并可能有助于糖尿病细胞替代策略的发展。
Heterozygous mutations in the human POLI-homeobox TCF2 (vHNF1, HNF1beta) gene are associated with maturity-onset diabetes of the young, type 5, and abnormal urogenital tract development. Recently, pancreas atrophies have been reported in several maturity-onset diabetes of the young type 5 patients, suggesting that TCF2 is required not only for adult pancreas function but also for its normal development. Tcf2-deficient mice die before gastrulation because of defective visceral endoderm formation. To investigate the role of this factor in pancreas development, we rescued this early lethality by tetraploid aggregation. We show that TCF2 has an essential function in the first steps of pancreas development, correlated with its expression domain that demarcates the entire pancreatic buds from the earliest stages. Lack of TCF2 results in pancreas agenesis by embryonic day 13.5. At earlier stages, only a dorsal bud rudiment forms transiently and expresses the transcription factors Ipf1 and HIxb9 but lacks the key transcription factor involved in the acquisition of a pancreatic fate, Ptf1a, as well as all endocrine precursor cells. Regional specification of the gut also is perturbed in Tcf2(-/-) embryos as manifested by ectopic expression of Shh and lack of Ihh and Ipf1 in the posterior stomach and duodenum. Our results highlight the requirement of Tcf2 for ensuring both accurate expression of key regulator molecules in the stomach-duodenal epithelium and proper acquisition of the pancreatic fate. This study provides further insights into early molecular events controlling pancreas development and may contribute to the development of cell-replacement strategies for diabetes.