Dissecting the role of the exon junction complex in embryonic corticogenesis

Duke University, Durham NC

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Abstract

? DESCRIPTION (provided by applicant): Embryonic neurogenesis is a tightly controlled process through which the cerebral cortex develops. During neurogenesis neural progenitors first undergo proliferative divisions, giving rise primarily to progenitors. As neurogenesis proceeds progenitor divisions increasingly give rise to neurons. Disruptions to this balanced production of progeny are associated with aberrations in cortical development, including microcephaly (reduced brain size). Recent human genetics studies reveal that mutations within components of the RNA binding exon junction complex (EJC) are clinically associated with neurodevelopmental disorders and in some cases microcephaly. We find that haploinsufficiency of EJC components in mice results in microcephaly, with precocious neuron production and apoptosis. Genetic ablation of p53 significantly, albeit partially, rescues microcephaly and neurogenesis phenotypes. This partial rescue implicates p53 as a major contributor to disease pathology, but suggests p53-independent mechanism also contribute. In this proposal we address two key questions: 1) What is the mechanism activating p53 following EJC impairment and 2) What are the p53- independent functions of the EJC which contribute to microcephaly. Recently, we have identified that ribosome biogenesis is disrupted in EJC mutant mice, an event which is well established to elicit a p53 response. Herein, propose to directly test if impaired ribosome biogenesis acts as a key mediator of p53 activation. Additionally, we will decipher the role of the EJC in modulating translation of fate determinant mRNAs as a p53-independent mechanism regulating neurogenesis.