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Transcriptional regulation of neural progenitor divisions and cell fate in the developing cortex

Award Number: R01MH129419
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/15/2023
PERIOD OF PERFORMANCE END DATE: 05/31/2028

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Transcriptional regulation of neural progenitor divisions and cell fate in the developing cortex - Summary The early expansion of the neural progenitor (NP) pool is a critical period, setting the stage for the development of the cerebral cortex. Alterations in NP proliferation during that period can have devastating consequences on neuron numbers and circuitry that could eventually lead to a variety of neurodevelopmental diseases such as autism, micro- and macrocephaly. Therefore, understanding the mechanisms that govern early NP expansion is central to understanding these diseases. Missense mutations or deletion of ZBTB7A lead to macrocephaly and intellectual disability but the mechanisms underlying these phenotypes are completely unknown. We discovered an enrichment for ZBTB7A in the nuclei of embryonic mouse NPs, and our Zbtb7a conditional KO (cKO) mouse model show increased cortical thickness at birth and an early expansion of the progenitor pool in embryonic cortices. Overexpression of ZBTB7A leads to opposite phenotypes, with premature differentiation of NPs. Next, we used CUT&RUN to identify ZBTB7A target genes during early cortical development. This analysis revealed that ZBTB7A binds to the promoters and enhancers of a regulon composed of transcription factors and cell-cycle regulators. We confirmed that ZBTB7A binds to the promoter of Hes5, and we observed that ZBTB7A can block Hes5 promoter activity in response to activated Notch. Finally, we used a novel in vivo BioID approach in E15 NPs to discover ZBTB7A interactors. This analysis suggests that ZBTB7A interacts with GATAD2A/B proteins, two components of the Nucleosome Remodeling and Deacetylase complex (NuRD) repressor complex. In this study, we will use a conditional knockout mouse model to further characterize how Zbtb7a impacts NP proliferation and the establishment of cortical architecture. In a second step, we will examine how ZBTB7A modulates Notch Signaling to control NP proliferation. We will use luciferase assays in primary NPs and in utero electroporation to test the relevance of ZBTB7A sub domains and how ZBTB7A patient mutations affect the expression of Notch targets. In a third step we will evaluate how ZBTB7A cooperates with the NuRD complex to regulate NP proliferation. For this we will use in vivo BioID as well as co-immunoprecipitation experiments to discover the composition of NuRD complexes interacting with ZBTB7A. We will repeat BioID experiments earlier in development and we will use co-immunoprecipitation to define which NuRD complex proteins associate with ZBTB7A in early NPs. The role of Gatad2b in NPs is completely unknown, therefore we will use IUE to test if knockdown of Gatad2b mimics NP proliferation phenotypes linked with Zbtb7a cKO, and to determine the requirement of Gatad2b in Zbtb7a overexpression phenotypes, including the repression of Notch targets. Altogether these studies will describe novel core principles that drive corticogenesis and will deepen our understanding of the etiology of 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: 2025 ( Subtotal = $415,000 )
2025	2025	SANFORD RESEARCH	801 BROADWAY N	FARGO	ND	58102	CASS	USA	Mental Health Research Grants	000	3	6/16/2025	NON-COMPETING CONTINUATION	$415,000
														Subtotal = $415,000

Issue Date FY: 2024 ( Subtotal = $415,000 )
2024	2024	SANFORD RESEARCH	801 BROADWAY N	FARGO	ND	58102	CASS	USA	Mental Health Research Grants	000	2	5/23/2024	NON-COMPETING CONTINUATION	$415,000
														Subtotal = $415,000

Issue Date FY: 2023 ( Subtotal = $415,000 )
2023	2023	SANFORD RESEARCH	2301 E 60TH ST N	SIOUX FALLS	SD	57104	MINNEHAHA	USA	Mental Health Research Grants	000	1	8/10/2023	NEW	$415,000
														Subtotal = $415,000

Grand Total All Awards = $1,245,000

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Transcriptional regulation of neural progenitor divisions and cell fate in the developing cortex

Award Number: R01MH129419

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/15/2023

PERIOD OF PERFORMANCE END DATE: 05/31/2028

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