Reduction of Ptf1a gene dosage causes pancreatic hypoplasia and diabetes in mice.
Reduction of Ptf1a gene dosage causes pancreatic hypoplasia and diabetes in mice.
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PTF1A基因剂量的降低会导致小鼠胰腺发育不全和糖尿病。
DOI：
10.2337/db07-1558
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发表时间：
2008-09
期刊：
影响因子：
7.7
通讯作者：
Uemoto, Shinji
中科院分区：
文献类型：
--
作者：
Fukuda, Akihisa;Kawaguchi, Yoshiya;Furuyama, Kenichiro;Kodama, Sota;Horiguchi, Masashi;Kuhara, Takeshi;Kawaguchi, Michiya;Terao, Mami;Doi, Ryuichiro;Wright, Christopher V. E.;Hoshino, Mikio;Chiba, Tsutomu;Uemoto, Shinji
目的：大多数胰腺内分泌细胞来源于表达Ptf1a的祖细胞。在人类中，Ptf1a的无义突变最近被确定为与胰腺发育不全相关的永久性新生儿糖尿病的原因。Ptf1a基因缺失的小鼠出生后不久死亡，无法进一步了解这种疾病的发病机制；因此，尚不清楚哺乳动物的胰腺内分泌功能在多大程度上依赖于Ptf1a。本研究旨在探讨Ptf1a对小鼠胰腺发育和功能的基因剂量效应。研究设计和方法-结合Ptf1a亚型和零等位基因以及Cre介导的谱系追踪，我们跟踪了Ptf1a表达减少的祖细胞的细胞命运，并分析了小鼠胰腺的发育和功能。结果-减少Ptf1a剂量会导致胰腺发育不良和糖耐量减低，并以剂量依赖的方式导致胰岛素分泌不足。在低形态突变小鼠中，胰腺芽大小很小，相当大比例的胰腺祖细胞被错误地指定为总胆管和十二指肠细胞。随着分枝形态发生和随后的外分泌细胞分化的生长减少和延迟。β细胞总数减少，非β胰岛细胞比例增加，α细胞与β细胞异常混杂。有趣的是，Pdx1的表达在早期胰腺祖细胞中降低，但在胰腺发生的中晚期升高到正常水平。结论：PTF1a的剂量对胰腺的规格、生长、β细胞总数、胰岛形态形成和内分泌功能至关重要。一些新生儿糖尿病可能由Ptf1a基因突变或单核苷酸多态引起，这些突变或单核苷酸多态降低了基因表达水平。
OBJECTIVE—Most pancreatic endocrine cells derive from Ptf1a-expressing progenitor cells. In humans, nonsense mutations in Ptf1a have recently been identified as a cause of permanent neonatal diabetes associated with pancreatic agenesis. The death of Ptf1a-null mice soon after birth has not allowed further insight into the pathogenesis of the disease; it is therefore unclear how much pancreatic endocrine function is dependent on Ptf1a in mammals. This study aims to investigate gene-dosage effects of Ptf1a on pancreas development and function in mice. RESEARCH DESIGN AND METHODS—Combining hypomorphic and null alleles of Ptf1a and Cre-mediated lineage tracing, we followed the cell fate of reduced Ptf1a-expressing progenitors and analyzed pancreas development and function in mice. RESULTS—Reduced Ptf1a dosage resulted in pancreatic hypoplasia and glucose intolerance with insufficient insulin secretion in a dosage-dependent manner. In hypomorphic mutant mice, pancreatic bud size was small and substantial proportions of pancreatic progenitors were misspecified to the common bile duct and duodenal cells. Growth with branching morphogenesis and subsequent exocrine cytodifferentiation was reduced and delayed. Total β-cell number was decreased, proportion of non-β islet cells was increased, and α-cells were abnormally intermingled with β-cells. Interestingly, Pdx1 expression was decreased in early pancreatic progenitors but elevated to normal level at the mid-to-late stages of pancreatogenesis. CONCLUSIONS—The dosage of Ptf1a is crucial for pancreas specification, growth, total β-cell number, islet morphogenesis, and endocrine function. Some neonatal diabetes may be caused by mutation or single nucleotide polymorphisms in the Ptf1a gene that reduce gene expression levels.
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