Graded reduction of Pafah1b1 (Lis1) activity results in neuronal migration defects and early embryonic lethality


Heterozygous mutation or deletion of the ß 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.

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Figure 1: Generation of Pafah1b1 mutant mice.
Figure 2: Early embryonic lethality of Pafah1b1-neo homozygous mice.
Figure 3: Morphological abnormalities in brains of Pafah1b1 heterozygous mutant mice.
Figure 4: Morphological abnormalities in brains of Pafah1b1 mutants.
Figure 5: In vivo analysis of neuronal migration.
Figure 6: In vitro analysis of neuronal migration.


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Correspondence to Anthony Wynshaw-Boris.

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Hirotsune, S., Fleck, M., Gambello, M. et al. Graded reduction of Pafah1b1 (Lis1) activity results in neuronal migration defects and early embryonic lethality. Nat Genet 19, 333–339 (1998).

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