Opposing actions of Arx and Pax4 in endocrine pancreas development
Opposing actions of Arx and Pax4 in endocrine pancreas development
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DOI：
10.1101/gad.269003
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发表时间：
2003-10-15
影响因子：
10.5
通讯作者：
Gruss, P
中科院分区：
文献类型：
--
作者：
Collombat, P;Mansouri, A;Gruss, P
基因编码的同源结构域的蛋白质可能参与内分泌胰腺的发展分离相结合的硅和巢式PCR方法。一种这样的转录因子Arx在α、β-前体细胞和δ细胞中的整个内分泌胰腺发育过程中表现出Ngn 3依赖性表达。我们已经在小鼠胚胎干细胞中使用基因靶向来产生Arx功能丧失小鼠。Arx缺陷动物以预期的孟德尔频率出生，但会出现早发性低血糖、脱水和虚弱，并在出生后2天死亡。Arx突变体胰腺的免疫组织学分析揭示了成熟内分泌α细胞的早发性损失，伴随着β细胞和δ细胞数量的增加，而胰岛形态保持完整。我们的研究表明Arx对α细胞命运获取的需求以及对β细胞和δ细胞命运的抑制作用，这与Pax 4在内分泌定型中的作用完全相反。使用多重逆转录酶PCR（RT-PCR），我们证明了积累的Pax 4和Arx的成绩单在Arx和Pax 4突变小鼠，分别。我们建议，适当的胰岛细胞规格的Arx和Pax 4的拮抗功能相关的胰腺水平的各自的成绩单。
Genes encoding homeodomain-containing proteins potentially involved in endocrine pancreas development were isolated by combined in silico and nested-PCR approaches. One such transcription factor, Arx, exhibits Ngn3-dependent expression throughout endocrine pancreas development in alpha, beta-precursor, and delta cells. We have used gene targeting in mouse embryonic stem cells to generate Arx loss-of-function mice. Arx-deficient animals are born at the expected Mendelian frequency, but develop early-onset hypoglycemia, dehydration, and weakness, and die 2 d after birth. Immunohistological analysis of pancreas from Arx mutants reveals an early-onset loss of mature endocrine alpha-cells with a concomitant increase in beta- and delta-cell numbers, whereas islet morphology remains intact. Our study indicates a requirement of Arx for alpha-cell fate acquisition and a repressive action on beta- and delta-cell destiny, which is exactly the opposite of the action of Pax4 in endocrine commitment. Using multiplex reverse transcriptase PCR (RT-PCR), we demonstrate an accumulation of Pax4 and Arx transcripts in Arx and Pax4 mutant mice, respectively. We propose that the antagonistic functions of Arx and Pax4 for proper islet cell specification are related to the pancreatic levels of the respective transcripts.