Molecular and cellular causes of severe heterotopia: Identifying new genes playing a role in radial glial cell.

ROMERO, D.M; BAHI-BUISSON, N; POIRIER, K; BIZZOTTO, S; CHELLY, J; ARTIGUENAVE, F; FRANCIS, F

Antibes Juan les Pins

Congreso; 21st Biennial Meeting of the International Society for Developmental Neuroscience; 2016

International Society of Developmental Neuroscience (ISDN)

Subcortical heterotopias are malformations of cortical development associated with epilepsy and intellectual disability, and characterized by the presence of ectopic neurons in the white matter. Mouse models of this disorder are rare, although mutations were identified in the microtubule-binding protein Eml1/EML1 in the spontaneous HeCo (?heterotopic cortex?) mouse, and in patients exhibiting severe ribbon-like heterotopia. HeCo mice have misplaced radial glial cell progenitors and ectopic proliferation during cortical development, which are likely to initiate non-cell autonomous migration defects. To explore the bases of this disorder, a cohort of patients (N=9) showing an EML1-like magnetic resonance imaging phenotype was selected for further investigations. These patients showed giant heterotopia with polymicrogyria, or periventricular nodular heterotopia and partial agenesis of corpus callosum. DNA samples from these patients were analyzed by exome sequencing. Candidate genes and pathways are being studied, particularly postsynaptic density genes also expressed in the ventricular zone with however, an unknown function in neuronal progenitors. Dlgap belongs to a membrane-associated guanylate kinase family. The role of this gene in early neurodevelopment has not been previously studied. Expression analyses confirm its presence in the ventricular zone at E13.5 and in the cortical plate in mouse brain. Cell biology studies in Neuro2A cells allow us to study neuronal progenitor characteristics in the presence, overexpression, and absence or mutation of the gene. Cell characteristics and potential protein partners are being followed in these cells. To further test its role, we are silencing Dlgap in wild-type embryos using in utero electroporation. Predicting the consequences of the human mutation (7 nucleotide insertion) on protein function using the structure and function prediction method I-Tasser, is revealing the extent of loss of Dlgap?s potential functions in progenitors.Our results will contribute to understanding of molecular and cellular mechanisms in progenitors, which when perturbed produce EML1-like severe heterotopia phenotypes.