IDENTIFICATION OF THE ARX MOLECULAR MECHANISMS IN CONTROLLING TELENCEPHALON DEVELOPMENT AND GABAERGIC NEURONAL MIGRATION: IMPLICATIONS FOR ARX DEPENDENT NEUROLOGICAL DISEASES

Mental retardation and epilepsy are common neuropathological conditions affecting 2-3% of the population. They often occur together and in many cases they are of genetic origin. Infantile spasms (IS) define a severe seizure disorder that usually starts early in life and in which seizures tend to occur in cluster. Once associated with hypsarrythmia on the EEG and developmental arrest they are classified as West syndrome. Importantly these related pathologies are largely resistant to treatment with medication and the lack of any good experimental model prevents the understanding of why these children regress and limit the therapeutic interventions. In the last years, it has been clearly recognized ARX gene mutations as a significant contributor to this large spectrum of diseases. In particular, Arx mutations account for 9.5% of all the familiar cases of non-syndromic X-linked mental retardation. Therefore, ARX deficiencies are believed to have a high impact on the society both for the relative high incidence and for the severe symptoms patients experience in early infancy. We have recently showed that a neuronal migration deficiency is at the basis of the brain malformations occurring in Arx deficient mice. We aim to investigate this issue identifying the target molecules whose altered expression leads to cell migration defects. These findings will allow to identify the Arx dependent molecular machinery controlling cell migration and will dramatically increase our possibilities of treating these disorders. In a second task, we will generate a new animal model for these disorders by expressing the polyalanine expansion mutation. This mutation is accounting for 40% of all the Arx dependent neurological disorder and exhibits peculiar pathogenetic mechanisms. These animals will represent an irreplaceable tool to investigate the molecular pathology and to offer a biological framework where the scientific community may establish successful therapeutic strategies.