Evolutionary conserved ARX-regulatory pathway in mammals and nematode to find a convergent druggable pathway damaged in neurodevelopmental disorders

The X-linked ARX gene encodes the Aristaless-related homeobox protein, which belongs to a subset of morphogenetic transcription factors with a crucial role in cerebral development and patterning. Mutations in ARX cause a wide spectrum of X-linked neurodevelopmental disorders including lissencephaly, a severe cortical malformation and a catastrophic epileptic encephalopathy with recurrent and resistant seizures. The health problem to find efficient treatments for ARX-related diseases highlights the need for understanding the components and pathways that regulate brain development. Because the neuronal functioning is maintained by a complex regulatory network, the use of powerful genetic models like mouse and worm can complement studies on human genetics and physiology by offering new opportunities to dissect complicated and evolutionary conserved regulatory circuits. Here we describe for the first time the conservation of an ARX-dependent disease-pathway among human, mouse and worm establishing a gene-phenotype association from one organism to another.