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Mechanisms of Abnormal Cranial Mesenchyme Morphogenesis in the Hectd1 mutant

Award Number: F31HD112200
ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 03/15/2023
PERIOD OF PERFORMANCE END DATE: 01/10/2025

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Mechanisms of Abnormal Cranial Mesenchyme Morphogenesis in the Hectd1 mutant - PROJECT SUMMARY While the cellular movements and shape changes that drive morphogenesis within the neural plate are well characterized, how morphogenesis of different cranial mesenchyme (CM) lineages contributes to neural fold elevation and how disruption of these mechanisms results in neural tube defects remains an open question. This application is based on the hypothesis that aberrant eHSP90 secretion and changes in the CM matrisome result in abnormal CM behavior, disrupting CM expansion in the Hectd1 mutant embryo. To model abnormal CM morphogenesis, a Hectd1 mouse mutant that fails neural tube closure will be used to determine both lineage relationship and gene expression changes that occur with CM morphogenesis leading to the neural tube defect. Aim 1 will assess how the neural crest (NC-CM) and paraxial mesoderm derived CM (PM-CM) interact in the Hectd1 mutant embryo leading to abnormal CM morphogenesis and failure of neural fold elevation. Both CM lineages are implicated as critical mediators of neural fold elevation. Analysis using SiMView adaptive light sheet microscope during normal CM expansion demonstrated distinct movements of the PM-CM and the NC- CM. Secondly, preliminary analysis of CM cells indicates that NC-CM cells are the primary migratory cells. Hectd1 is required in the NC-CM for neural fold elevation, but the PM-CM also fails to expand in the Hectd1 mutant. Therefore, lineage tracing and conditional genetic models of Hectd1 will be used to test the contribution of the NC-CM and PM-CM to abnormal morphogenesis in the Hectd1 mutant line using live imaging of in vitro CM explant assays. Lastly, increased extracellular HSP90 (eHSP90) secretion is observed in NC-CM cells of our mutant mouse. This potential mechanism for their abnormal interaction leading to the neural tube defect will be tested with additional live imaging of CM explants with the addition of eHSP90. Aim 2 will assess the changes in matrisome gene expression of the CM during neural fold elevation. The CM cells are embedded in an extracellular matrix (ECM), which undergoes expansion during neural fold elevation. The ECM is critical to morphogenesis in many systems. Embryonic tissues from key timepoints will be analyzed using bulk RNA sequencing to identify extracellular matrix genes implicated in CM morphogenesis in neural fold elevation. Bioinformatics analyses will identify differentially expressed genes, and in situ hybridization experiments will map critical differential gene expression across different time points. Successful completion of these studies will transform our understanding of the mechanisms leading to neural tube defects and address a crucial gap in our understanding of neural tube formation.


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 = -$16,695 )
2026	2024	CHILDREN'S RESEARCH INSTITUTE	111 MICHIGAN AVE NW	WASHINGTON	DC	20010	DISTRICT OF COLUMBIA	USA	Child Health and Human Development Extramural Research	000	2	1/27/2026	NON-COMPETING CONTINUATION	-$16,695
														Subtotal = -$16,695

Issue Date FY: 2025 ( Subtotal = -$4,950 )
2025	2024	CHILDREN'S RESEARCH INSTITUTE	111 MICHIGAN AVE NW	WASHINGTON	DC	20010	DISTRICT OF COLUMBIA	USA	Child Health and Human Development Extramural Research	000	2	3/20/2025	NON-COMPETING CONTINUATION	-$4,950
														Subtotal = -$4,950

Issue Date FY: 2024 ( Subtotal = $45,969 )
2024	2024	CHILDREN'S RESEARCH INSTITUTE	111 MICHIGAN AVE NW	WASHINGTON	DC	20010	DISTRICT OF COLUMBIA	USA	Child Health and Human Development Extramural Research	001	2	5/7/2024	NON-COMPETING CONTINUATION	$1,580
2024	2024	CHILDREN'S RESEARCH INSTITUTE	111 MICHIGAN AVE NW	WASHINGTON	DC	20010	DISTRICT OF COLUMBIA	USA	Child Health and Human Development Extramural Research	000	2	2/15/2024	NON-COMPETING CONTINUATION	$44,389
														Subtotal = $45,969

Issue Date FY: 2023 ( Subtotal = $44,389 )
2023	2023	CHILDREN'S RESEARCH INSTITUTE	111 MICHIGAN AVE NW	WASHINGTON	DC	20010	DISTRICT OF COLUMBIA	USA	Child Health and Human Development Extramural Research	001	1	3/15/2023	NEW	$0
2023	2023	CHILDREN'S RESEARCH INSTITUTE	111 MICHIGAN AVE NW	WASHINGTON	DC	20010	DISTRICT OF COLUMBIA	USA	Child Health and Human Development Extramural Research	000	1	3/15/2023	NEW	$44,389
														Subtotal = $44,389

Grand Total All Awards = $68,713

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Mechanisms of Abnormal Cranial Mesenchyme Morphogenesis in the Hectd1 mutant

Award Number: F31HD112200

ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 03/15/2023

PERIOD OF PERFORMANCE END DATE: 01/10/2025

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