The cellular roles of the lissencephaly gene LIS1, and what they tell us aboutbrain development
- Department of Pathology and Cell Biology, Center for Neurobiology and Behavior, Columbia University College of Physicians and Surgeons, New York, New York 10032 USA
This extract was created in the absence of an abstract.
Lissencephaly is a severe brain developmental disease characterized by mislocalization of cortical neurons. This class of diseases has received considerable recent attention for their promise in shedding light on the mechanisms underlying the massive waves of neural progenitor cell migration required for brain development. Classical lissencephaly results from sporadic mutations in the human LIS1 gene, which has been implicated in regulating the microtubule motor protein cytoplasmic dynein. This connection supports a role for LIS1 in cell motility, and suggests that defects in dyneinmediated movement are responsible for lissencephaly. This article reviews evidence regarding the cellular defects contributing to classical lissencephaly, with emphasis on recent live analysis of LIS1-deficient neural progenitor cell motility in brain tissue.
Lissencephaly
The lissencephalopathies are brain developmental diseases characterized by decreased cortical complexity (Crome 1956; Barkovich et al. 1991; Dobyns and Truwit 1995). The surface of the brain is relatively smooth, giving rise to the name of the condition, which translates from Greek to “smooth brain.” Classical, or type I lissencephaly, is caused by sporadic mutations in the LIS1 gene (Reiner et al. 1993; Lo Nigro et al. 1997). X-linked lissencephaly is caused by both familial and sporadic mutations in the DCX gene, which encodes the protein doublecortin (des Portes et al. 1998; Gleeson et al. 1998).
These diseases have received considerable attention during the past half decade for a number of reasons. Brain size is generally greater in the lissencephalopathies than in microcephalic conditions. This distinction suggests that progenitor cell proliferation plays less of a role in lissencephaly. Differentiated neurons are produced, but many are mislocalized, typically in a broad ectopic lamina internal to the normal cortical layers (Stewart et al. 1975). Together these observations have suggested that LIS1 and DCX may play roles in neural progenitor cell migration, a very …
