Hnf1b controls pancreas morphogenesis and the generation of Ngn3+ endocrine progenitors
Hnf1b controls pancreas morphogenesis and the generation of Ngn3+ endocrine progenitors
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DOI：
10.1242/dev.110759
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发表时间：
2015-03-01
期刊：
影响因子：
4.6
通讯作者：
Haumaitre, Cecile
中科院分区：
文献类型：
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作者：
De Vas, Matias G.;Kopp, Janel L.;Haumaitre, Cecile
人类HNF1B基因的杂合突变与青年5型成熟型糖尿病（MODY5）和胰腺发育不全相关。在小鼠中，Hnf1b杂合突变体不表现出任何表型，而整个上胚层中的纯合缺失导致与异常肠道区域化相关的胰腺发育不全。在这里，我们研究Hnf1b在胰腺发育过程中的具体作用，在关键的发展阶段，使用组成和诱导条件失活的方法。Hnf1b早期缺失导致胰腺多能祖细胞（MPC）池减少，这是由于增殖减少和凋亡增加。缺乏Hnf1b无论是在第一次或第二次转型与胆囊管。导管细胞表现出异常极性和几种囊性疾病基因的表达减少，其中一些我们确定为新型Hnf 1b靶点。值得注意的是，我们表明，Glis3，参与导管形态和内分泌细胞发育的转录因子，是下游Hnf1b。此外，观察到腺泡细胞的损失和异常分化。引人注目的是，Hnf1b在不同时间点的失活导致整个胚胎发生过程中Ngn 3（+）内分泌前体的缺乏。我们进一步表明，Hnf1b占据新的Ngn 3推定的调控序列在体内。因此，Hnf1b在控制胰腺MPC扩张、腺泡细胞身份、导管形态发生和内分泌前体产生的调控网络中起着至关重要的作用。我们的研究结果揭示了Hnf1b在内分泌细胞特化中的一个未被重视的需求，并提出了MODY5患者糖尿病发病的机制解释。
Heterozygous mutations in the human HNF1B gene are associated with maturity-onset diabetes of the young type 5 (MODY5) and pancreas hypoplasia. In mouse, Hnf1b heterozygous mutants do not exhibit any phenotype, whereas the homozygous deletion in the entire epiblast leads to pancreas agenesis associated with abnormal gut regionalization. Here, we examine the specific role of Hnf1b during pancreas development, using constitutive and inducible conditional inactivation approaches at key developmental stages. Hnf1b early deletion leads to a reduced pool of pancreatic multipotent progenitor cells (MPCs) due to decreased proliferation and increased apoptosis. Lack of Hnf1b either during the first or the secondary transitions is associated with cystic ducts. Ductal cells exhibit aberrant polarity and decreased expression of several cystic disease genes, some of which we identified as novel Hnf1b targets. Notably, we show that Glis3, a transcription factor involved in duct morphogenesis and endocrine cell development, is downstream Hnf1b. In addition, a loss and abnormal differentiation of acinar cells are observed. Strikingly, inactivation of Hnf1b at different time points results in the absence of Ngn3(+) endocrine precursors throughout embryogenesis. We further show that Hnf1b occupies novel Ngn3 putative regulatory sequences in vivo. Thus, Hnf1b plays a crucial role in the regulatory networks that control pancreatic MPC expansion, acinar cell identity, duct morphogenesis and generation of endocrine precursors. Our results uncover an unappreciated requirement of Hnf1b in endocrine cell specification and suggest a mechanistic explanation of diabetes onset in individuals with MODY5.