Mutations in ARX result in several defects involving GABAergic neurons

Abstract

Genetic investigations of X-linked mental retardation have demonstrated the implication of ARX in a wide spectrum of disorders extending from phenotypes with severe neuronal migration defects, such as lissencephaly, to mild or moderate forms of mental retardation without apparent brain abnormalities, but with associated features of dystonia and epilepsy. These investigations have in recent years directed attention to the role of this gene in brain development. Analysis of its spatio-temporal localization profile revealed expression in telencephalic structures at all stages of development, mainly restricted to populations of GABA-containing neurons. Furthermore, studies of the effects of ARX loss of function either in humans or in lines of mutant mice revealed varying defects, suggesting multiple roles of this gene during development. In particular, Arx has been shown to contribute to almost all fundamental processes of brain development: patterning, neuronal proliferation and migration, cell maturation and differentiation, as well as axonal outgrowth and connectivity. In this review, we will present and discuss recent findings concerning the role of ARX in brain development and how this information will be useful to better understand the pathophysiological mechanisms of mental retardation and epilepsy associated with ARX mutations.

Analysis of transcriptional codes for zebrafish dopaminergic neurons reveals essential functions of Arx and Isl1 in prethalamic dopaminergic neuron development

“…As Arx has been shown to play a crucial role in GABAergic development (Friocourt and Parnavelas, 2010), our data indicate that Arx function is conserved in this respect. However, such function appears to be restricted to the prethalamic area in zebrafish, because all other GABAergic forebrain territories develop normally.…”

Pathogenesis and new candidate treatments for infantile spasms and early life epileptic encephalopathies: A view from preclinical studies

“…Arx is a transcriptional factor involved in the migration of GABAergic progenitors and early commitment of cholinergic neurons (Friocourt and Parnavelas 2010). Arx genetic defects have been found in various early life epileptic encephalopathies, including West syndrome, and may or may not show pronounced structural brain and other abnormalities, as in X-linked lissencephaly with abnormal genitalia (XLAG) (Dobyns et al 1999; Kato et al 2003; Stromme et al 2002).…”

Cross-species pharmacological characterization of the allylglycine seizure model in mice and larval zebrafish

“…Furthermore, GABA-deficient epileptic syndromes also exist in genetic forms of epilepsy in humans or mice. Some examples include the following: 1) X-linked lissencephaly with abnormal genitalia, resulting from ARX (Aristaless Related Homeobox) mutations, with patients often displaying intractable epilepsy [49][50][51]; 2) DLX1 (Distal-less Homeobox 1) mutant mice [52]; 3) loss of GABApositive cortical interneurons in the uPAR (Urokinase Plasminogen Activator Receptor) knockout mouse [53,54]; and 4) dysregulated GABA-mediated synaptic inhibition as a result of disorganized hippocampal interneurons in Lis1 (Lissencephaly 1) mutant mice [55][56][57][58].…”