LPIAT1 regulates arachidonic acid content in phosphatidylinositol and is required for cortical lamination in mice.
LPIAT1 regulates arachidonic acid content in phosphatidylinositol and is required for cortical lamination in mice.
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DOI：
10.1091/mbc.e12-09-0673
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发表时间：
2012-12
影响因子：
3.3
通讯作者：
Arai H
中科院分区：
文献类型：
--
作者：
Lee HC;Inoue T;Sasaki J;Kubo T;Matsuda S;Nakasaki Y;Hattori M;Tanaka F;Udagawa O;Kono N;Itoh T;Ogiso H;Taguchi R;Arita M;Sasaki T;Arai H
花生四烯酸（AA）在磷脂酰肌醇（PI）中显著富集。使用溶血磷脂酰肌醇酰基转移酶1（选择性地将AA并入PI）敲除小鼠的研究表明，含AA的PI在大脑发育过程中的皮层分层和神经元迁移中起着至关重要的作用。膳食花生四烯酸（AA）在婴儿的生长，神经元发育和认知功能中起作用。AA是显着丰富的磷脂酰肌醇（PI），在哺乳动物中的生物膜的重要组成部分，然而，生理意义的AA含有PI仍然未知。在RNA干扰为基础的遗传筛选使用秀丽隐杆线虫，我们最近克隆mboa-7作为一个酰基转移酶，选择性地将AA到PI。在这里，我们表明，溶血磷脂酰肌醇酰基转移酶1（LPIAT 1，也被称为MBOAT 7），最接近的哺乳动物同源物，在小鼠大脑发育中起着至关重要的作用。Lpiat 1 −/−小鼠在使用花生四烯酸-CoA作为酰基供体时几乎没有表现出LPIAT活性，并且在PI和PI磷酸盐中表现出AA含量降低。Lpiat 1 −/−小鼠在一个月内死亡，并显示大脑皮层和海马萎缩。免疫组织化学分析显示，E18.5 Lpiat 1 −/−小鼠皮质分层紊乱，神经元迁移延迟。LPIAT 1缺陷还导致皮质中的神经元过程紊乱和体外神经突生长减少。总之，这些结果表明，AA-含有PI/PI磷酸盐在小鼠脑发育过程中的正常皮质分层中起重要作用。
Arachidonic acid (AA) is remarkably enriched in phosphatidylinositol (PI). Studies using knockout mice of lysophosphatidylinositol acyltransferase 1, which selectively incorporates AA into PI, reveal that AA-containing PI plays a crucial role in cortical lamination and neuronal migration during brain development. Dietary arachidonic acid (AA) has roles in growth, neuronal development, and cognitive function in infants. AA is remarkably enriched in phosphatidylinositol (PI), an important constituent of biological membranes in mammals; however, the physiological significance of AA-containing PI remains unknown. In an RNA interference–based genetic screen using Caenorhabditis elegans, we recently cloned mboa-7 as an acyltransferase that selectively incorporates AA into PI. Here we show that lysophosphatidylinositol acyltransferase 1 (LPIAT1, also known as MBOAT7), the closest mammalian homologue, plays a crucial role in brain development in mice. Lpiat1−/− mice show almost no LPIAT activity with arachidonoyl-CoA as an acyl donor and show reduced AA contents in PI and PI phosphates. Lpiat1−/− mice die within a month and show atrophy of the cerebral cortex and hippocampus. Immunohistochemical analysis reveals disordered cortical lamination and delayed neuronal migration in the cortex of E18.5 Lpiat1−/− mice. LPIAT1 deficiency also causes disordered neuronal processes in the cortex and reduced neurite outgrowth in vitro. Taken together, these results demonstrate that AA-containing PI/PI phosphates play an important role in normal cortical lamination during brain development in mice.