Journal
NEUROSCIENCE LETTERS
Volume 439, Issue 1, Pages 100-105Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.neulet.2008.04.096
Keywords
reeler; neuronal migration; disabled-1; lis1; platelet activating factor acetylhydrolase; neocortex
Categories
Funding
- NINDS NIH HHS [R01 NS042616-01A2, R01 NS042616] Funding Source: Medline
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Reelin, an extracellular protein that signals through the Dab1 adapter protein, and Lis1 regulate neuronal migration and cellular layer formation in the brain. Loss of Reelin and reduction in Lis1 activity in mice or humans results in the disorganization of cortical structures. Lis1, the product of the Pafah1b1 gene associates with Alphal (the product of the Pafah1b3 gene) and Alpha2 (the product of the Pafah1b2 gene) to form the Pafah1b heterotrimeric complex. This complex interacts biochemically and genetically with the Reelin pathway, however, the role of Alphal and Alpha2 in brain development is poorly understood. We previously demonstrated that compound mutations of Pafah1b1 with genes in Reelin pathway result in layering defects and the appearance of hydrocephalus in double mutant mice. Here, we generate triple mouse mutants to investigate the effect of individual Pafah1b Alpha subunits on cellular layer formation and hydrocephalus. We found that Pafah1b3 mutations exacerbate the layering defects, whereas Pafah1b2 mutations strongly suppress the hydrocephalus phenotype of compound mutant mice. The data indicate that the two Pafah1b2 Alpha subunits have profoundly different effects on brain development and interact in a significantly different manner with the Reelin signaling pathway. (c) 2008 Elsevier Ireland Ltd. All rights reserved.
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