Pbx1 inactivation disrupts pancreas development and in Ipf1-deficient mice promotes diabetes mellitus
Pbx1 inactivation disrupts pancreas development and in Ipf1-deficient mice promotes diabetes mellitus
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DOI：
10.1038/ng860
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发表时间：
2002-04-01
期刊：
影响因子：
30.8
通讯作者：
Cleary, ML
中科院分区：
文献类型：
--
作者：
Kim, SK;Selleri, L;Cleary, ML
Pbx 1是同源结构域转录因子（1，2）的TALE（三氨基酸环延伸）类的成员，其是异源寡聚蛋白复合物的组分，被认为调节发育基因表达并维持分化的细胞状态（3）。体外研究（4，5）表明Pbx 1调节Ipf 1（也称为Pdx 1）的活性，Ipf 1是一种Para-Hox同源域转录因子（6，7），是小鼠和人类胰腺发育和功能所需的（8-10）。为了研究Pbx 1在胰腺发育和功能中的体内作用，我们检测了Pbx 1缺陷小鼠的胰腺Pbx 1表达、形态发生、细胞分化和功能（11，12）。Pbx 1（-/-）胚胎在胚胎第15天或E16天死亡前胰腺发育不全，外分泌和内分泌细胞分化明显缺陷。在这些胚胎中，胰腺形态发生和分化的重要调节因子IsI 1和Atoh 5的表达严重减少。Pbx 1（+/-）成人有胰岛畸形，糖耐量受损和低胰岛素血症。因此，Pbx 1对正常胰腺发育和功能至关重要。对转杂合子Pbx 1（+/-）Ipf 1（+/-）小鼠的分析揭示了Pbx 1和Ipf 1之间的体内遗传相互作用，这对出生后胰腺功能至关重要;这些小鼠与Pbx 1（+/-）或Ipf 1（+/-）小鼠不同，出现了年龄依赖性显性糖尿病。影响Ipf 1蛋白的突变可能会促进小鼠和人类的糖尿病（13-16）。这项研究表明，Pbx 1活性的扰动也可能促进糖尿病的易感性。
Pbx1 is a member of the TALE (three-amino acid loop extension) class of homeodomain transcription factors(1,2), which are components of hetero-oligomeric protein complexes thought to regulate developmental gene expression and to maintain differentiated cell states(3). In vitro studies(4,5) have shown that Pbx1 regulates the activity of Ipf1 (also known as Pdx1), a Para-Hox homeodomain transcription factor(6,7) required for the development and function of the pancreas in mice and humans(8-10). To investigate in vivo roles of Pbx1 in pancreatic development and function, we examined pancreatic Pbx1 expression, and morphogenesis, cell differentiation and function in mice deficient(11,12) for Pbx1. Pbx1(-/-) embryos had pancreatic hypoplasia and marked defects in exocrine and endocrine cell differentiation prior to death at embryonic day (E) 15 or E16. In these embryos, expression of IsI1 and Atoh5, essential regulators of pancreatic morphogenesis and differentiation, was severely reduced. Pbx1(+/-) adults had pancreatic islet malformations, impaired glucose tolerance and hypoinsulinemia. Thus, Pbx1 is essential for normal pancreatic development and function. Analysis of trans-heterozygous Pbx1(+/-) Ipf1(+/-) mice revealed in vivo genetic interactions between Pbx1 and Ipf1 that are essential for postnatal pancreatic function; these mice developed age-dependent overt diabetes mellitus, unlike Pbx1(+/-) or Ipf1(+/-) mice. Mutations affecting the Ipf1 protein may promote diabetes mellitus in mice and humans(13-16). This study suggests that perturbation of Pbx1 activity may also promote susceptibility to diabetes mellitus.