# Understanding the Role of EIF4A2 in Neurodevelopment

> **NIH NIH K08** · MASSACHUSETTS GENERAL HOSPITAL · 2024 · $234,630

## Abstract

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.

## Key facts

- **NIH application ID:** 10949537
- **Project number:** 1K08NS138691-01
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Anna Ruth Duncan
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $234,630
- **Award type:** 1
- **Project period:** 2024-08-10 → 2029-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10949537

## Citation

> US National Institutes of Health, RePORTER application 10949537, Understanding the Role of EIF4A2 in Neurodevelopment (1K08NS138691-01). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10949537. Licensed CC0.

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