# An Evolutionarily Conserved RNA Binding Protein Critical for Proper Neuronal Function Regulates Lipid Storage and Metabolic Pathways

> **NIH NIH F31** · EMORY UNIVERSITY · 2024 · $48,974

## Abstract

PROJECT SUMMARY
Intellectual disability (ID), which affects approximately 1-3% of the human population, is characterized by
neurological deficiencies. Genetic forms of ID are often associated with an increased risk of obesity compared
to the general population and often individuals diagnosed with ID have various forms of metabolic defects.
Common metabolic defects include an increase in body fat, high triglyceride levels, and high blood sugar. The
underlying link(s) between neuronal dysfunction and metabolism are not yet clear. The Corbett and Moberg labs
co-discovered a non-syndromic autosomal recessive form of ID caused by mutations in the gene encoding an
evolutionarily conserved and ubiquitously expressed zinc-finger, polyadenosine RNA-binding protein (RBP),
ZC3H14. A Drosophila model has been invaluable to study the function of ZC3H14. Initial work revealed that
Nab2, the Drosophila orthologue of ZC3H14, while ubiquitously expressed, is required specifically in neurons to
support proper axon guidance, locomotion, and olfactory memory. Further studies identified a robust genetic
interaction between Nab2 and Mettl3, the catalytic component of the m6A methyltransferase complex, which
deposits the most abundant post-transcriptional modification on RNA. An unbiased RNA Seq analysis comparing
control and nab2 mutant flies identified a set of metabolic transcripts that are altered when Nab2 is lost. My
preliminary data reveal that loss of Nab2 causes increases both in lipid droplet size in the Drosophila fat body
(human adipose tissue equivalent) and the steady state levels of two metabolic transcripts: dilp2 and dilp5.
Drosophila insulin like peptides (Dilp), Dilp2 and Dilp5, are released from the insulin-producing cells in the brain
into the hemolymph where they travel to the fat body to regulate lipid storage and larval metabolism. As many
patients with ID also have various metabolic defects, my project investigates how loss of ZC3H14/Nab2 results
in metabolic dysfunction. Thus, I will test the hypothesis that the evolutionarily conserved RNA binding protein
Nab2 regulates lipid storage and mRNA transcripts critical for proper metabolic function. I will test this hypothesis
through the following complementary but independent specific aims: 1) Use lipidomics coupled with a cell-type
specific RNAi to define the effect of Nab2 loss on lipids in larvae; 2) Test the effect of Nab2 loss on dilp2/dilp5
mRNA levels and Pi3K/insulin signaling; and 3) Define cell-type specific requirement for Mettl3 in regulating lipid
droplet size and examine levels of m6A modifications on dilp2 and dilp5 in Nab2null larvae. Successful completion
of the proposed Aims will provide insights into novel molecular mechanisms of ZC3H14/Nab2 in regulating fat
storage and target RNAs critical for proper metabolic function. This proposal supports our long-term goal of
exploiting a Drosophila model of ID to understand how loss of an RBP in brain neurons can elicit physiological
ch...

## Key facts

- **NIH application ID:** 10996958
- **Project number:** 1F31NS135980-01A1
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Jordan Goldy
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $48,974
- **Award type:** 1
- **Project period:** 2024-09-01 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10996958

## Citation

> US National Institutes of Health, RePORTER application 10996958, An Evolutionarily Conserved RNA Binding Protein Critical for Proper Neuronal Function Regulates Lipid Storage and Metabolic Pathways (1F31NS135980-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10996958. Licensed CC0.

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