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Investigating the RNA-Regulatory Activities of the RNA Exosome during Human Motor Neuron Differentiation

Award Number: F31NS143348
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 07/03/2025
PERIOD OF PERFORMANCE END DATE: 06/30/2028

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Investigating the RNA-Regulatory Activities of the RNA Exosome during Human Motor Neuron Differentiation - Project Summary: Accurate stem cell differentiation requires precise gene regulation at both the transcriptional and post- transcriptional levels. While the transcriptional activation networks governing cellular differentiation are well characterized, the mechanisms by which post-transcriptional control of gene expression alters the transcriptome to confer cellular identity remain poorly understood. The RNA exosome, an essential and ubiquitous post- transcriptional ribonuclease complex, plays a significant role in cellular differentiation by modulating steady-state level of RNA to maintain the pluripotent potential of stem cell and progenitor populations. Depletion of a single RNA exosome subunit results in precocious differentiation in several cell types, and deletion of any subunit is embryonically lethal. Although the RNA exosome is conserved from yeast to humans and plays essential roles in all cells, recessive mutations in RNA exosome subunit genes disproportionately affect neuronal tissues and give rise to severe neurodevelopmental disorders (NDDs). For instance, mutations in the EXOSC3 gene, encoding a structural cap subunit of the RNA exosome, cause Pontocerebellar Hypoplasia Type 1b (PCH1b), a prenatal onset NDD associated with severe spinal motor neuron defects that emerge during embryonic development. Similarly, a mutation in the EXOSC4 gene, which encodes a core subunit of the RNA exosome, was recently linked to a distinct NDD with a comparable spinal motor neuropathy phenotype. These findings suggest that spinal motor neurons are uniquely susceptible to RNA exosome-mediated post-transcriptional regulation defects. However, the RNA exosome has not been studied in human neurons or during neuronal differentiation. To investigate the function of the RNA exosome during neuronal differentiation, I will utilize human induced pluripotent stem cells (hiPSCs), engineered by my lab via CRISPR technology, to model RNA exosome- linked motor neuron diseases, including severe PCH1b (EXOSC3-G31A), mild PCH1b (EXOSC3-G191C), and a novel NDD linked to a mutation in EXOSC4 (EXOSC4-L187P). To study the RNA exosome in a disease- relevant context, I will investigate the impact of pathogenic EXOSC3/4 mutations on human spinal motor neuron differentiation using a 2D cell culture method. I hypothesize that disease-linked mutations in EXOSC3/4 alter the function of the RNA exosome during motor neuron differentiation, leading to an accumulation of pathogenic RNA species that cause spinal motor neuropathy. This research will provide a comprehensive analysis of how pathogenic mutations in RNA exosome subunit genes impact post-transcriptional regulation during human neuronal differentiation and provide insight into pathological mechanisms underlying RNA-mediated motor neuropathy.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $46,168 )
2026	2026	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90033	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	6/30/2026	NON-COMPETING CONTINUATION	$46,168
2026	2025	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90033	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	4/17/2026	NEW	$0
														Subtotal = $46,168

Issue Date FY: 2025 ( Subtotal = $45,241 )
2025	2025	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90033	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	6/30/2025	NEW	$45,241
2025	2025	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90033	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	1	6/30/2025	NEW	$0
														Subtotal = $45,241

Grand Total All Awards = $91,409

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Investigating the RNA-Regulatory Activities of the RNA Exosome during Human Motor Neuron Differentiation

Award Number: F31NS143348

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 07/03/2025

PERIOD OF PERFORMANCE END DATE: 06/30/2028

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