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The Journal of Neuroscience, April 25, 2007, 27(17):4786-4798; doi:10.1523/JNEUROSCI.0417-07.2007
Neurobiology of Disease
Inactivation of Arx, the Murine Ortholog of the X-Linked Lissencephaly with Ambiguous Genitalia Gene, Leads to Severe Disorganization of the Ventral Telencephalon with Impaired Neuronal Migration and Differentiation
Elena Colombo,1 * Patrick Collombat,2 * Gaia Colasante,1 Marta Bianchi,1 Jason Long,3 Ahmed Mansouri,2 John L. R. Rubenstein,3 andVania Broccoli1 1Stem Cell Research Department, San Raffaele Scientific Institute, 20132 Milan, Italy, 2Department of Molecular Cell Biology, Max-Planck Institute for Biophysical Chemistry, 37077 Goettingen, Germany, and 3Nina Ireland Laboratory of Developmental Neurobiology, Department of Psychiatry, University of California, San Francisco, San Francisco, California 94158
Correspondence should be addressed to Vania Broccoli, Stem Cell Research Department, Dibit–San Raffaele Scientific Institute, Via Olgettina 58, 20132 Milan, Italy. Email: broccoli.vania{at}hsr.it
ARX loss-of-function mutations cause X-linked lissencephaly with ambiguous genitalia (XLAG), a severe neurological condition that results in profound brain malformations, including microcephaly, absence of corpus callosum, and impairment of the basal ganglia. Despite such dramatic defects, their nature and origin remain largely unknown. Here, we used Arx mutant mice as a model to characterize the cellular and molecular mechanisms underlying the basal ganglia alterations. In these animals, the early differentiation of this tissue appeared normal, whereas subsequent differentiation was impaired, leading to the periventricular accumulation of immature neurons in both the lateral ganglionic eminence and medial ganglionic eminence (MGE). Both tangential migration toward the cortex and striatum and radial migration to the globus pallidus and striatum were greatly reduced in the mutants, causing a periventricular accumulation of NPY+ or calretinin+ neurons in the MGE. Arx mutant neurons retained their differentiation potential in vitro but exhibited deficits in morphology and migration ability. These findings imply that cell-autonomous defects in migration underlie the neuronal localization defects. Furthermore, Arx mutants lacked a large fraction of cholinergic neurons and displayed a strong impairment of thalamocortical projections, in which major axon fiber tracts failed to traverse the basal ganglia. Altogether, these results highlight the critical functions of Arx in promoting neural migration and regulating basal ganglia differentiation in mice, consistent with the phenotype of XLAG patients.
Key words: forebrain; interneurons; neural migration; striatum; development; GABA; thalamocortical projections; cell fate
Received May 12, 2006; revised March 5, 2007; accepted March 6, 2007.
Correspondence should be addressed to Vania Broccoli, Stem Cell Research Department, Dibit–San Raffaele Scientific Institute, Via Olgettina 58, 20132 Milan, Italy. Email: broccoli.vania{at}hsr.it
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