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Mutations in the human ARX gene, which encodes a highly conserved homeodomain containing transcription factor, have recently been identified in children with various neurological disorders, including infantile spasms syndrome and mental retardation (ISSXlMR; Stromme et al., 2002; Kato et al., 2004), dystonia (Bienvenu et al., 2002) and X-linked lissencephaly with ambiguous genitalia (XLAG) (Kitamura et al., 2002). Lissencephaly is characterized by smooth cerebral surface (agyria or pachygyria), abnormally thick cortex, deficient cortical layering and diffuse neural heterotopias (Kato and Dobyns, 2003). Compelling experimental evidences have shown that this phenotype arise by an aberrant radial migration, a mechanism by which normally neuroblasts reach their final location in the cortical field (Walsh and Goffinet, 2000). The murine ortholog Arx is expressed in the nervous system primarily during embryonic development and is characterized by a dynamic expression pattern, appearing during both early shaping of the forebrain and later major events of neural migrations and cell-type specification. Herein, I show that Arx presents a different pattern of expression in the dorsal and ventral forebrain. In fact, while it is strongly expressed in the proliferating ventricular zone (VZ) of the developing cortex; Arx shows strong expression in differentiated cells of the mantle zones of the lateral and medial ganglionic eminences (LGE and MGE). The LGE and MGE are sources of tangentially migrating young neurons spreading into the developing cortical plate and fated to differentiate into GABAergic interneurons. Arx expression is detectable in the interneurons of the adult cerebral cortex, restricted to a population ofGABAergic neurons (Colombo et aI., 2004) To gain insight into the potential function of Arx gene during development, loss-offunction mutant mice were generated by homologous recombination in embryonic stem (ES) cells by Collombat et al. (2003). Arx mutant mice die perinatally due to hypoglygemia related to pancreatic defects. Arx deficient brains are found dramatically altered, exhibiting poorly developed olfactory bulbs and reduced cerebral cortex and hippocampus (Kitamura et aI., 2002). Moreover, GABAergic neurons originating from the sub-pallium exhibit an aberrant migration toward the cerebral cortex, inducing a decrease in the number of cortical GABAergic intemeurons (Kitamura et aI., 2002). Unfortunately, the perinatal death of these mice do not allow any correlation of these specific alterations with the neurological manifestations observed in human. I ~ake advantage ofArx 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 appear normal, whereas subsequent neurogenesis is impaired, leading to an accumulation of periventricular immature neurons in both the LGE and' MGE. Both tangential migration toward the cortex and striatum, as well as radial migration to the globus pallidus and striatum, are dramatically affected in mutants, causing an accumulation of NPY+ or calretinin+ neurons in the MGE periventricular domain. Notably, Arx mutant neurons retain their differentiation potential in vitro, but fail to show a sustained migration ability. This migration alteration is further associated with an abnormal morphology of Arx mutant cells. My findings imply that Arx dependent cell-autonomous defects in migration activity may impinge on the final neuronal localization and maturation in situ. Furthermore, Arx mutants lack a large fraction of cholinergic neurons and display a strong impairment of thalamo-cortical projections where major axon fiber tracts failed to traverse the basal ganglia. Altogether, these results underline a critical function of Arx in promoting neural migration and regulating neural differentiation of basal telencephalic structures in mice and suggest a similar role in human as outlined in XLAG patients.