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Molecular Regulation of Palate Development

Award Number: R01DE033890
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: 03/04/2024
PERIOD OF PERFORMANCE END DATE: 12/31/2028

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Molecular Regulation of Palate Development - Abstract Submucous cleft palate (SMCP), defined by abnormal attachment of palatal muscles with intact oral and nasal mucosa, is a common craniofacial birth defect that disrupts the essential function of the soft palate for swallowing, causing feeding difficulties, middle ear dysfunction leading to hearing loss, and lifetime speech problems. Humans have five pairs of palatal muscles that all attach to the palatine aponeurosis, a fan-like dense fibrous connective tissue comprising the core of the soft palate that connects to the hard palate bone. Whereas the palatal muscles are derived from embryonic pharyngeal mesoderm, all connective tissues in the soft palate, including the palatine aponeurosis, tendons, and the muscle connective tissues that are embedded within and ensheathing the muscles, develop from cranial neural crest cell (CNCC) derived mesenchyme. Studies of limb muscle development have identified the embryonic muscle connective tissue as an important source of signals for patterning both the nascent muscles and tendons. However, how muscle connective tissue and tendon cells are specified from a common mesenchymal progenitor population and how they regulate muscle and tendon development remain unclear. We found that the Foxf2 and Foxd1 transcription factors exhibit complementary and partly overlapping patterns of expression along the medial- lateral axis of the embryonic soft palate mesenchyme at the onset of palatal myogenesis, with Foxf2 expression enriched in medial mesenchymal progenitors and with Foxd1 strongly expressed in the mesenchyme cells in the muscle-forming lateral region of the embryonic soft palate in mice. We demonstrate that Foxf2-deficient mice exhibit specific soft palate defects, including mispositioned palatal muscles and failure of palatine aponeurosis formation. Expression of Foxd1 and muscle-associating mesenchyme markers are ectopically activated in the medial mesenchymal progenitor cells in Foxf2 mutant embryonic soft palate. Furthermore, Foxd1 heterozygosity substantially rescues palatine aponeurosis formation and integration with the tensor veli palatini (TVP) muscles in Foxf2 mutant mice. On the other hand, homozygous disruption of Foxd1 causes aberrant splitting and abnormal attachment of TVP muscles to the pterygoid plate. Our central hypothesis is that Foxf2 and Foxd1 act antagonistically to regulate the specification and differentiation of distinct connective tissue lineages from the CNCC-derived soft palate mesenchyme to guide the morphogenesis and integration of palatal muscles. We propose comprehensive experimental studies to gain unprecedented understanding of the cellular and molecular mechanisms regulating soft palate connective tissue development and palatal muscle morphogenesis. Data from these studies provide a rich resource for uncovering mechanisms coordinating development and integration of musculoskeletal tissues and will lead to improvement in diagnosis and treatment of SMCP and other musculoskeletal 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 = $589,163 )
2026	2026	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Oral Diseases and Disorders Research	000	3	12/17/2025	NON-COMPETING CONTINUATION	$589,163
														Subtotal = $589,163

Issue Date FY: 2025 ( Subtotal = $664,175 )
2025	2025	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Oral Diseases and Disorders Research	000	2	12/3/2024	NON-COMPETING CONTINUATION	$597,758
2025	2025	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Oral Diseases and Disorders Research	001	2	5/5/2025	NON-COMPETING CONTINUATION	$66,417
														Subtotal = $664,175

Issue Date FY: 2024 ( Subtotal = $664,175 )
2024	2024	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Oral Diseases and Disorders Research	000	1	3/4/2024	NEW	$664,175
														Subtotal = $664,175

Grand Total All Awards = $1,917,513

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Molecular Regulation of Palate Development

Award Number: R01DE033890

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: 03/04/2024

PERIOD OF PERFORMANCE END DATE: 12/31/2028

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