Deletion of peptide amidation enzymatic activity leads to edema and embryonic lethality in the mouse
Deletion of peptide amidation enzymatic activity leads to edema and embryonic lethality in the mouse
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DOI：
10.1016/j.ydbio.2005.09.001
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发表时间：
2005-11-15
影响因子：
2.7
通讯作者：
Pintar, JE
中科院分区：
文献类型：
--
作者：
Czyzyk, TA;Ning, Y;Pintar, JE
肽酰甘氨酸酰胺化单加氧酶（PAM）催化肽激素的cooh末端酰胺化。我们之前在发育中的啮齿动物的几个区域发现了PAM的高表达。为了确定PAM在小鼠胚胎发生过程中的功能，我们制备了PAM基因的零突变体。纯合突变体在e14.5和e15.5之间在子宫内死亡，伴有严重的水肿，可能是由于心血管缺陷。这些缺陷包括主动脉和颈动脉变薄，并且与最近表征的肾上腺髓质素（AM）基因KO非常相似，尽管PAM KO胚胎中存在升高的免疫反应性AM。在PAM突变体胚胎中未检测到肽酰胺化活性，如果在小鼠中存在其他肽酰胺化机制，则没有预期的am样表型的调节。尽管提出了修饰肽对神经元细胞增殖的贡献，但在致死性纯合突变胚胎中未观察到神经母细胞增殖的改变。突变型PAM等位基因杂合的小鼠发育正常，表达几种酰胺肽的野生型水平，尽管PAM活性和PAM蛋白的野生型水平只有野生型的一半。尽管如此，与同窝对照相比，老龄杂合小鼠（10 ~ 10个月）肥胖和轻度葡萄糖耐受不良的发生率均有所增加。因此，在小鼠发育过程中，PAM的消融证明了该基因的基本功能，而在成人中，PAM活性的改变可能是更微妙的生理效应的基础。(C) 2005爱思唯尔公司版权所有。
Peptidylglycine alpha-amidating monooxygenase (PAM) catalyzes the COOH-terminal amidation of peptide hormones. We previously had found high expression of PAM in several regions of the developing rodent. To determine the function of PAM during mouse embryogenesis, we produced a null mutant of the PAM gene. Homozygous mutants die in utero between e14.5 and e15.5 with severe edema that is likely due to cardiovascular deficits. These defects include thinning of the aorta and carotid arteries and are very similar to those of the recently characterized adrenomedullin (AM) gene KO despite the presence of elevated immunoreactive AM in PAM KO embryos. No peptide amidation activity was detected in PAM mutant embryos, and there was no moderation of the AM-like phenotype that could be expected if any alternative peptide amidation mechanism exists in the mouse. Despite the proposed contribution of amidated peptides to neuronal cell proliferation, no alteration in neuroblast proliferation was observed in homozygous mutant embryos prior to lethality. Mice heterozygous for the mutant PAM allele develop normally and express wildtype levels of several amidated peptides despite having one half the wildtype levels of PAM activity and PAM protein. Nonetheless, both an increase in adiposity and a mild glucose intolerance developed in aged (>10 months) heterozygous mice compared to littermate controls. Ablation of PAM thus demonstrates an essential function for this gene during mouse development, while alterations in PAM activity in the adult may underlie more subtle physiologic effects. (C) 2005 Elsevier Inc. All rights reserved.