Characterization of highly conserved molecular pathways involved in neurodevelopmental disorders (NDDs)

Introduction. Neurodevelopmental disorder (NDD) genes play a role across a range of biological functions, including transcriptional regulation, epigenetic modification, and synaptic structure and functioning. Although NDD genes are functionally diverse, they are highly inter-connected and control multiple processes, including neuronal morphology, synaptic plasticity and neuronal homeostasis. In this framework, the identification of secondary molecular determinants contributing to disease phenotypes is essential for dissecting the pathogenic mechanisms. The complexity of the intricate disease network underlying NDD pathology requires a reductionist approach and the use of a simplified animal model such as C. elegans offers a particularly suitable tool for understanding the function of highly conserved genes involved in neuronal function. Methods & Results. Here we report on a multidisciplinary study by using the C. elegans mutant strain collection (CNR-IBBR-CELITABASE) to identify mechanistically conserved pathways under the control of Aristaless-related homeobox (ARX) protein. This is a transcription factor encoded by a highly evolutionary conserved gene involved in a wide spectrum of NDDs, including cortical malformations, epileptic encephalopathy with pharmaco-resistant seizures and intellectual disability. Starting from the homologous gene relationship between ARX and its worm (alr-1) counterpart, we carried out computational analysis of ARX/alr1 targets and in vivo studies in worm mutants. Applying this complementary strategy, we identified several evolutionary conserved ARX-bound genes. Of them, 18 are disease genes mutated in NDD patients with movement disorders and involved in different neuronal functions (e.g. axon guidance and neuron maturation). Conclusions. Our results proved the highly conserved history of ARX demonstrating how the use of C.elegans constitute a powerful experimental strategy for the identification of unanticipated evolutionarily conserved regulatory circuits damaged in NDDs