Eml1 is involved in primary cilium assembly at early stages of cortical development.

UZQUIANO, A; ROMERO, D.M; HOULLIER, A; DINGLI, F; ARRAS, G; LOEW, D; BAHI-BUISSON, N; FRANCIS, F

Nara

Congreso; 22nd Biennial Meeting of the International Society for Developmental Neuroscience; 2018

International Society of Developmental Neuroscience (ISDN)

The cerebral cortex is a highly organized structure whose development depends ondiverse neuronal progenitors, producing postmitotic neurons that migrate totheir final positions in the cortical plate. Progenitor behavior and dynamics are crucial to assure correct neuronal output and cortex formation, and when perturbed give rise to cortical malformations.We arestudying the HeCo mouse, which is a model for subcortical heterotopia, amalformation in which many neurons are found mislocalized within the whitematter and beneath the normotopiccortex. The microtubule-associated proteinEml1/EML1 was found to be mutated in these mice as well as in three familiespresenting severe atypical heterotopia (Kielar et al., 2014, Shaheen et al.,2017). In early stages of corticogenesis, aberrantly positioned neuronal progenitors were found cycling outside their proliferative zone (the ventricular zone, VZ). In order to shed light into the mechanisms leading to ectopic progenitors, we are studying the VZ of these mice, focusing on the main progenitor cell type residing in this zone: the apical radial glia (aRG). Using avariety of approaches (genetic tools, confocal coronal and en face imaging,electron microscopy) we have identified centrosome and primary cilia defects inthe HeCo VZ, associated with abnormal aRG endfeet in interphase, whichare larger and less numerous. Supporting primary cilia anomalies in Eml1 mutantconditions, patient fibroblasts also show a decrease in number and length ofthese organelles. Our combined data suggest a novel role for Eml1 in primarycilia assembly. Additionally, mass spectrometry (MS) analyses for Eml1 interacting partners, as well as exome-sequencing performed to identify new genes mutated in patients presenting a similar form of heterotopia, point towards ciliary Eml1 partners. Gene ontology analyses of MS data are guiding futureexperiments to dissect the intracellular mechanisms by which primary cilia failto form properly in Eml1 mutant conditions.