Date of Award

1-1-2011

Document Type

Campus Access Dissertation

Department

Biological Sciences

First Advisor

Deanna S Smith

Abstract

Lissencephaly is a devastating developmental brain disorder caused by LIS1 haploinsufficiency. This developmental brain abnormality is characterized by decreased brain folding, cognitive and motor impairment, and progressively worsening seizures. From earlier studies it is clear that Lis1 regulates key events in mitosis and migration of neurons during embryonic brain development (1). Lis1 and its binding partner, Ndel1, both bind to the motor protein cytoplasmic dynein (2). This microtubule-based motor is best known for its role in retrograde axonal transport (3), but also clearly functions with Lis1 and Ndel1 to control distinct developmental processes. If embryonic defects are solely responsible for the symptoms associated with neurological disorders such as lissencephaly then post-partum treatment options are limited. However, Lis1 and Ndel1 expression remain high in the adult brain, suggesting the possibility of a role in mature neurons. Here I present evidence that Lis1 and Ndel1 regulate key aspects of dynein-dependent axon transport in adult neurons. Lis1 overexpression stimulates transport of lysosomes and mitochondria, but Lis1 point mutants with reduced dynein or Ndel1 binding are unable to do so and in fact are inhibitory. Lis1 reduction by RNAi inhibits axon transport of these organelles. Transport is also perturbed in DRG neurons from adult Lis1+/- mice which contain a null mutation in a single Lis1 allele and are considered a model for human lissencephaly. Finally, I present evidence that Ndel1 phosphorylation by Cdk5 regulates axon organelle transport. My findings identify an important role for Lis1 and Ndel1 in mature neurons and suggest that defects in this regulatory system may contribute to neurological disorders.

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