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Transcriptional and epigenetic regulation of neural progenitorfates

Award Number: R21NS151067
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/02/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2027

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Transcriptional and epigenetic regulation of neural progenitorfates - In vertebrate development, the brain forms from the ectoderm germ layer during gastrulation. When this process goes awry, structural and functional neurodevelopmental disorders occur. A key goal of developmental biology is therefore to understand the fundamental process whereby the brain develops from the ectoderm. The generally accepted hypothesis for early brain development in vertebrates is known as the “activation- transformation model” and posits that ectoderm is first activated to anterior neural fates by mesoderm-derived signals and then transformed to posterior fates by gradients of secreted factors, but it remains unclear how these signals are ‘interpreted’ by the ectoderm to produce progenitors for distinct brain structures. A major barrier to progress in this area has been the lack of molecular data for ectodermal cells in the process of undergoing activation-transformation. Challenges in ascertaining the identify of cells at early stages (when they do not yet express genes indicative of specific fates), have left us to infer the details of early events based on read-outs later in development. We recently overcame this barrier by carrying out a scMultiome time course analysis of activation-transformation in zebrafish, thereby providing comprehensive molecular profiles of cells during this process. We have resolved neural progenitors from neural crest, placodal and epidermal progenitors, and – focusing on the developing hindbrain – we have identified distinct progenitor populations at the end of gastrulation. These early progenitor populations do not yet express hindbrain-restricted genes, yet they are transcriptionally distinct from each other, and computational analyses reveal that each progenitor population is related to distinct later-stage cell types that form different hindbrain structures. Our scMultiome data represent the first comprehensive molecular analysis of cells undergoing activation-transformation and position us to address key unanswered questions: What classes of genes characterize the early hindbrain progenitor populations? What genes are activated by activation-transformation signals and what are their roles? Our preliminary data also revealed that the early progenitor populations are only beginning to establish unique patterns of chromatin accessibility, raising the questions: What drives these chromatin changes? How do they ensure the formation of distinct neural progenitor populations? We will answer these questions in the context of our hypothesis that activation-transformation signals alter the chromatin state by inducing accessible regulatory elements that drive distinct gene expression programs in neural progenitors. The successful completion of our project will address current knowledge gaps and provide vital information to better understand, diagnose, and – ultimately – treat, neurodevelopmental disorders.


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 = $429,000 )
2026	2026	THE REGENTS OF THE UNIVERSITY OF COLORADO	13001 E 17TH PL STE F428	AURORA	CO	80045	ADAMS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	9/2/2026	NEW	$429,000
														Subtotal = $429,000

Grand Total All Awards = $429,000

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Transcriptional and epigenetic regulation of neural progenitorfates

Award Number: R21NS151067

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/02/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2027

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