Cellular consequences of mutations in the mouse homologs of the human lissencephaly genes LIS1 and ARX

Ilya Michael Nasrallah, University of Pennsylvania

Abstract

Migration of neurons is a fundamental process of development of the mammalian neocortex. This migration occurs along one of two pathways, the radial and non-radial pathways. We hypothesize that defects in normal neural migration caused by mutations in genes critical to neural migration result in human neurodevelopmental disorders. Defects in radial neural migration have been previously identified in gene mutations that lead to human lissencephaly, a family of neurodevelopmental disorders characterized by severe structural and functional abnormalities of the neocortex. Using Lis1 +/- mice, a common model of human lissencephaly caused by mutations in the Lissencephaly1 (LIS1 ) gene, we show that Lis1 +/- mice also exhibit a decrease in non-radial cell migration (NRCM) in vivo and in vitro that is primarily cell-autonomous. This decrease in NRCM is caused by a decrease in the rate of active migration and an increase in the time migrating neurons spend at rest. Furthermore, we find that Lis1 +/- non-radially migrating neurons have an abnormal morphology consisting of a longer leading process and less frequent branching. We also present evidence that these effects on migration may be conserved in humans with LIS1 mutations, who have an apparent delay in NRCM. Mutations in Aristaless-related homeobox (ARX ) have more recently been linked to human neurodevelopmental disease, including lissencephaly and infantile spasms syndrome with mental retardation. Studies of the murine homolog, Arx , have shown that it is required for normal NRCM. In order to understand how mutations in ARX affect neural migration, we generated a model for one form of ARX mutation, a polyalanine (polyA) expansion. Expression of polyA-expanded Arx in vitro and in vivo causes the formation of ubiquitinated nuclear inclusions. The formation of these inclusions is suppressed by coexpression of the Hsp70 molecular chaperone. Furthermore, we demonstrate that expression of polyA-expanded Arx increases cell death in vitro . These data suggest that misfolding of polyA-expanded Arx results in cellular toxicity that contributes to defects in neural development.

Recommended Citation

Ilya Michael Nasrallah, "Cellular consequences of mutations in the mouse homologs of the human lissencephaly genes LIS1 and ARX" (January 1, 2004). Dissertations from ProQuest. Paper AAI3125882.
http://repository.upenn.edu/dissertations/AAI3125882