Hirotsune S, Fleck M W, Gambello M J, Bix G J, Chen A, Clark G D, Ledbetter D H, McBain C J, Wynshaw-Boris A
Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Nat Genet. 1998 Aug;19(4):333-9. doi: 10.1038/1221.
Heterozygous mutation or deletion of the beta subunit of platelet-activating factor acetylhydrolase (PAFAH1B1, also known as LIS1) in humans is associated with type I lissencephaly, a severe developmental brain disorder thought to result from abnormal neuronal migration. To further understand the function of PAFAH1B1, we produced three different mutant alleles in mouse Pafah1b1. Homozygous null mice die early in embryogenesis soon after implantation. Mice with one inactive allele display cortical, hippocampal and olfactory bulb disorganization resulting from delayed neuronal migration by a cell-autonomous neuronal pathway. Mice with further reduction of Pafah1b1 activity display more severe brain disorganization as well as cerebellar defects. Our results demonstrate an essential, dosage-sensitive neuronal-specific role for Pafah1b1 in neuronal migration throughout the brain, and an essential role in early embryonic development. The phenotypes observed are distinct from those of other mouse mutants with neuronal migration defects, suggesting that Pafah1b1 participates in a novel pathway for neuronal migration.
人类血小板活化因子乙酰水解酶（PAFAH1B1，也称为LIS1）β亚基的杂合突变或缺失与I型无脑回畸形有关，这是一种严重的发育性脑部疾病，被认为是由异常的神经元迁移导致的。为了进一步了解PAFAH1B1的功能，我们在小鼠Pafah1b1中产生了三种不同的突变等位基因。纯合缺失小鼠在胚胎植入后不久的胚胎发育早期死亡。具有一个无活性等位基因的小鼠表现出皮质、海马和嗅球紊乱，这是由细胞自主神经元途径导致的神经元迁移延迟引起的。Pafah1b1活性进一步降低的小鼠表现出更严重的脑紊乱以及小脑缺陷。我们的结果证明了Pafah1b1在整个大脑神经元迁移中具有至关重要的、剂量敏感的神经元特异性作用，以及在早期胚胎发育中的重要作用。观察到的表型与其他具有神经元迁移缺陷的小鼠突变体不同，这表明Pafah1b1参与了一种新的神经元迁移途径。
