Understanding the Role of EIF4A2 in Neurodevelopment

PROJECT SUMMARY/ ABSTRACT Neurodevelopmental disorders (NDD) are common, affecting 3% of the global population with emerging data suggesting that many are attributable to a genetic etiology. In the DEAD-box family of RNA Helicases, 18% of the genes have been shown to be important for neurodevelopment with pathogenic variants leading to

a range of NDD. Through the proposed NIH Mentored Clinical Scientist Career Development (K08) Award, the role of the DEAD-Box encoding gene, EIF4A2, in interneuron development will be evaluated Pathogenic variants in EIF4A2 lead to a NDD characterized by intellectual disability, epilepsy, hypotonia and structural changes in the developing brain. Modelling of EIF4A2 missense variants in Drosophila

demonstrates that both loss- and gain-of-EIF4A2-function alter neurodevelopment. However, the mechanisms by which EIF4A2 loss- or gain-of-function alter brain development and the timing of these events have yet to be determined. Preliminary studies utilizing acute CRISPR gene editing of zebrafish demonstrate that loss of

EIF4A2 leads to a reduction in interneuron number, suggesting reduced GABA interneuron generation, impaired differentiation and/or alterations in migration may have occurred. In this K08 proposal, the role of EIF4A2 in interneuron development and the impact of loss and gain of function on this process will be studied in zebrafish. Zebrafish are an optimal model system since they permit

rapid genetic editing, are excellent for live imaging, and have well conserved stages of neurodevelopment. The following 5 groups will be compared: wild type controls (WT), eif4a2 +/-, eif4a2 -/- , WT with overexpressed EIF4A2 mRNA, and eif4a2 -/- with EIF4A2 mRNA rescue. In Aim 1, EIF4A2 loss- and gain-of-function

zebrafish models will be generated and their phenotypes characterized. In Aim 2, using these models, the role of EIF4A2 in interneuron progenitor cell generation and differentiation will be examined. In Aim 3, the impact of loss- and gain-of EIF4A2 function on GABA interneuron migration will be assessed. By understanding

EIF4A2’s role in each aspect of interneuron development, targets of opportunity for future investigation will be identified for both EIF4A2-associated NDD and more common conditions involving interneuron dysfunction. International experts in neurobiology, zebrafish, genetics, and neurogenetics will provide mentorship for

this proposed Career Development Award. The primary mentor will be Ann Poduri, MD, MPH. The Scientific Advisory Committee will be composed of Kevin Staley, MD, David Sweetser, MD, PhD, Gordon Fishell, PhD, and Pankaj Agrawal, MD, MMSc. They will provide guidance for both the short-term goal of understanding the

role that EIF4A2 plays in neurodevelopment and the long-term goal of improving neurodevelopmental outcomes of infants and children with both rare and common causes of NDD.