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The role of the Foxi3 transcription factor in craniofacial microsomia

Award Number: R01DE032244
ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2025
PERIOD OF PERFORMANCE END DATE: 01/31/2028

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The role of the Foxi3 transcription factor in craniofacial microsomia - PROJECT SUMMARY Craniofacial abnormalities are some of the most common birth defects. Although cleft lip and/or palate and craniosynostosis are the most common craniofacial defects, craniofacial microsomia (CFM) is estimated to be the third most prevalent cranial anomaly, occurring at between 1 in 3000 – 1 in 6000 live births. Although the symptoms of CFM can vary widely in severity, they share a variety of features consistent with abnormal development of first and second pharyngeal arches, including a shortening of the mandible, microtia, preauricular tags and epibulbar dermoids. These defects are typically, but not exclusively unilateral, and although some families presenting with CFM have been identified, most are considered sporadic and have no genetic diagnosis. Difficulties in understanding the origins of CFM include its heterogeneity, the lack of clear underlying molecular mechanisms and the paucity of good animal models for these disorders. We have identified a transcription factor, Foxi3, that is expressed early and broadly in pharyngeal ectoderm and endoderm, and is later restricted to the pharyngeal pouches and clefts. Foxi3 mutant mice show severe defects in most pharyngeal arch derivatives – for example, the mutants lack much of the lower jaw, and have a complete loss of the middle ear ossicles and the external ear. Recently, our colleagues found over 20 human variants in Foxi3 associated with craniofacial defects including CFM and microtia, and our preliminary data suggests these defects can be modeled in mice carrying some of these variants. Moreover, the Gata3 transcription factor, which has been associated with CFM in genome-wide association studies, is co-expressed with Foxi3 in several developing cranial tissues and has also recently been shown to cause CFM phenotypes when mutated in mice. This raises the possibility that Foxi3 and Gata3 interact genetically during craniofacial development. In this proposal, we will first attempt to create a mouse model of CFM using Foxi3 mutant alleles created in our lab and Gata3 mutant alleles characterized by our collaborators. Second, we will perform a bioinformatic analysis of the gene regulatory networks controlled by Foxi3 and Gata3, by analyzing gene expression in pharyngeal tissue from Foxi3 homozygous mutants, heterozygous mutant and wild type mice, and by performing CUT&RUN on pharyngeal tissue to identify direct targets of Foxi3 and Gata3. Finally, we will address the role of Foxi3 during early craniofacial development by performing conditional deletions of Foxi3 in pharyngeal ectoderm and endoderm and determining its contribution to normal craniofacial development in each tissue.


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: 2027 ( Subtotal = $742,801 )
2027	2025	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Oral Diseases and Disorders Research	000	3	10/27/2026	NON-COMPETING CONTINUATION	$742,801
														Subtotal = $742,801

Issue Date FY: 2026 ( Subtotal = -$169,033 )
2026	2026	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Oral Diseases and Disorders Research	001	4	1/29/2026	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$516,391
2026	2026	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Oral Diseases and Disorders Research	004	4	4/30/2026	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$57,377
2026	2025	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Oral Diseases and Disorders Research	003	3	4/9/2026	NON-COMPETING CONTINUATION	-$583,053
2026	2025	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Oral Diseases and Disorders Research	000	3	1/28/2026	NON-COMPETING CONTINUATION	$0
2026	2024	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Oral Diseases and Disorders Research	002	2	4/9/2026	NON-COMPETING CONTINUATION	-$159,748
														Subtotal = -$169,033

Issue Date FY: 2025 ( Subtotal = $583,053 )
2025	2025	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Oral Diseases and Disorders Research	000	3	1/13/2025	NON-COMPETING CONTINUATION	$524,748
2025	2025	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Oral Diseases and Disorders Research	001	3	5/6/2025	NON-COMPETING CONTINUATION	$58,305
														Subtotal = $583,053

Issue Date FY: 2024 ( Subtotal = $576,285 )
2024	2024	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Oral Diseases and Disorders Research	001	2	6/11/2024	NON-COMPETING CONTINUATION	$47,043
2024	2024	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Oral Diseases and Disorders Research	000	2	1/2/2024	NON-COMPETING CONTINUATION	$529,242
														Subtotal = $576,285

Issue Date FY: 2023 ( Subtotal = $591,370 )
2023	2023	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Oral Diseases and Disorders Research	000	1	3/7/2023	NEW	$591,370
														Subtotal = $591,370

Grand Total All Awards = $2,324,476

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The role of the Foxi3 transcription factor in craniofacial microsomia

Award Number: R01DE032244

ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2025

PERIOD OF PERFORMANCE END DATE: 01/31/2028

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