Conditional knockout of the Menkes disease copper transporter demonstrates its critical role in embryogenesis.
Conditional knockout of the Menkes disease copper transporter demonstrates its critical role in embryogenesis.
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DOI：
10.1371/journal.pone.0043039
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Petris MJ
中科院分区：
文献类型：
--
作者：
Wang Y;Zhu S;Weisman GA;Gitlin JD;Petris MJ
过渡金属铜（Cu）是一种广泛的生化过程所需的酶辅因子。它的重要性由Menkes病证明，Menkes病是一种X连锁的铜缺乏症，其特征在于神经，心血管和骨骼系统的缺陷，并且由ATP 7A铜转运蛋白突变引起。某些ATP7A突变也会导致X连锁脊髓性肌萎缩症3型（SMAX3），其特征是缺乏潜在的全身性铜缺乏的神经肌肉缺陷。虽然这些ATP 7A相关疾病的理解将明显受益于允许组织特异性缺失ATP 7A基因的动物模型，但目前还不存在这样的模型。在这项研究中，我们产生了一个floxed小鼠模型，允许使用Cre重组酶的Atp7a基因的条件删除。Atp7a基因的缺失导致半合子雄性胚胎的形态和血管缺陷以及子宫内死亡。杂合子缺失导致女性活产减少50%，产后致死率高。这些研究证明了Atp7a基因在小鼠胚胎发育中的重要作用，并为理解ATP7A在铜代谢和疾病中的组织特异性作用建立了一个强大的模型。
The transition metal, copper (Cu), is an enzymatic cofactor required for a wide range of biochemical processes. Its essentiality is demonstrated by Menkes disease, an X-linked copper deficiency disorder characterized by defects in nervous-, cardiovascular- and skeletal systems, and is caused by mutations in the ATP7A copper transporter. Certain ATP7A mutations also cause X-linked Spinal Muscular Atrophy type 3 (SMAX3), which is characterized by neuromuscular defects absent an underlying systemic copper deficiency. While an understanding of these ATP7A-related disorders would clearly benefit from an animal model that permits tissue-specific deletion of the ATP7A gene, no such model currently exists. In this study, we generated a floxed mouse model allowing the conditional deletion of the Atp7a gene using Cre recombinase. Global deletion of Atp7a resulted in morphological and vascular defects in hemizygous male embryos and death in utero. Heterozygous deletion in females resulted in a 50% reduction in live births and a high postnatal lethality. These studies demonstrate the essential role of the Atp7a gene in mouse embryonic development and establish a powerful model for understanding the tissue-specific roles of ATP7A in copper metabolism and disease.
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