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Principal Investigator: Jennifer Leslie Fish
Organization: UNIVERSITY OF MASSACHUSETTS LOWELL
Fiscal Year: 2024
Award: $455,939
Funding agency: National Institute of Dental and Craniofacial Research
PROJECT SUMMARY
Craniofacial malformations are among the most common human birth defects. Tissues of the head and neck
derive from the pharyngeal arches (PAs). PAs are transient developmental structures formed by mesenchymal
populations, the neural crest (NC) and mesoderm, that migrate in between epithelial layers, the surface
ectoderm and foregut endoderm. Our work focuses on the jaw skeleton, which derives from NC of the first
pharyngeal arch (PA1). Pharyngeal epithelia have at least 3 critical roles in jaw development: 1) segmenting
PA1 from PA2, 2) providing signals that support patterning and proliferation of PA1 mesenchyme, and 3)
subsequently differentiating into tissue derivatives of the ear. To better understand how pharyngeal epithelia
regulate jaw development, we investigate the development and morphogenesis of the first pharyngeal pouch
(pp1) and first pharyngeal cleft (pc1), which segment PA1 and PA2. The signaling factor, Fgf8, is expressed in
both pp1 and pc1. Our previous work has shown that jaw development is sensitive to Fgf8 dosage and exhibits
directional asymmetry, with the left side being more severely affected than the right. Similar directional
asymmetry trends are observed in human craniofacial malformations. We also found that Fgf8-mediated
defects of the jaw skeleton are associated with 1) alterations to patterning of PA1 NC and 2) malformations in
both pp1 and pc1. Our data indicate that Fgf8 is critical to pp1 and pc1 development, but the specific cellular
mechanisms mediated by Fgf8 are unknown. In our previous work, we defined 4 stages of pp1 and pc1
morphogenesis, including an extended period of contact between pp1 and pc1, which is disrupted in Fgf8
mutants. The interaction between pp1 and pc1 is transient, as the two epithelia later separate to complete their
differentiation. We hypothesize that Fgf8 is required to mediate regional cell identity in pp1 and pc1 to form a
boundary and mediate epithelial extension. In Aim 1, we will further explore how Fgf8 dosage impacts
epithelial cell biology. A second aspect of our previous work that remains unexplained is the mechanism
underlying directional asymmetry in Fgf8 mutant jaws. In Aim 2, we will further explore how Fgf8 dosage
contributes to directional asymmetry in jaw development. We hypothesize that progenitors of the heart field
migrating through PA1 provide small amounts of Fgf8 that buffer PA1 development when Fgf8 dosage is low.
Finally, in Aim 3, we will begin to explore how Fgf8 dosage is further modulated through splice variants. Fgf8
mRNA exhibits splice variants. The two most common protein isoforms, FGF8a and FGF8b, have distinct ERK
signaling activity. These data suggest that mRNA splicing may modulate Fgf8 dosage beyond the cis-
regulatory mechanisms we have previously studied. We will use both in vivo and in vitro models to test our
Aims. This work has implications for craniofacial disease syndromes that also include heart defects, such as
CHARGE and DiGeorge (22q11 deletion) syndromes. These syndromes also exhibit asymmetry in jaw and ear
defects.
Terms: <22q11><22q11 Chromosomal Microdeletion Syndrome><22q11 Deletion Syndrome><22q11.2 deletion syndrome><22q11.2DS><22q11DS><Affect><Autosomal dominant Opitz G/BBB syndrome><Birth><Birth Defects><Body Tissues><Branchial arch structure><Buffers><CHARGE syndrome><Cardiac defect><Cayler cardiofacial syndrome><Cell Body><Cell Communication and Signaling><Cell Function><Cell Junctions><Cell Physiology><Cell Process><Cell Signaling><Cells><Cellular Function><Cellular Physiology><Cellular Process><Cellular biology><Chromosome 22q11.2 deletion syndrome><Congenital Abnormality><Congenital Anatomical Abnormality><Congenital Defects><Congenital Deformity><Congenital Malformation><Craniofacial Abnormalities><Data><Defect><Development><Di George syndrome><DiGeorge Syndrome><DiGeorge anomaly><DiGeorge sequence><Diagnosis><Disease><Disease Outcome><Disorder><Ear><Ectoderm><Eligibility><Eligibility Determination><Embryo><Embryonic><Endoderm><Environment><Epithelial Cells><Epithelium><Exhibits><Face><Facial asymmetry><First Pharyngeal Arch><Foregut><Genetic Models><Genotype><Head and Neck><Head and neck structure><Heart><Hemifacial Microsomia><Human><Institution><Intercellular Junctions><Intracellular Communication and Signaling><Isoforms><Jaw><Left><Mediating><Mesenchymal><Mesenchymas><Mesenchyme><Mesoderm><Messenger RNA><Modern Man><Molecular><Molecular and Cellular Biology><Morphogenesis><Morphology><Neural Crest><Neural Crest Cell><Neural tube><Nuclear><Outcome><Parturition><Pattern><Penetrance><Pharangeal Arch><Pharyngeal pouch><Pharyngeal structure><Pharynx><Population><Primitive foregut structure><Proliferating><Protein Isoforms><Protocol Screening><RNA Splicing><Regulation><Research><Role><Sedlackova syndrome><Severities><Shapes><Shprintzen syndrome><Side><Signal Transduction><Signal Transduction Systems><Signaling><Skeleton><Splicing><Structure><Subcellular Process><Surface Ectoderm><Syndrome><Testing><Throat><Tissues><Variant><Variation><Visceral Arches><Work><biological signal transduction><branchial arch><cell biology><conotruncal anomaly face syndrome><craniofacial><craniofacial anomalies><craniofacial defects><craniofacial disorder><craniofacial malformation><craniofacies><developmental><dosage><faces><facial><familial third and fourth pharyngeal pouch syndrome><first pharyngeal pouch><heart defect><improved><in vitro Model><in vivo><insight><mRNA><malformation><migration><morphogenetic process><mutant><pharyngeal arch><pharyngeal patterning><pharyngeal pouch syndrome><progenitor><skeletons><social role><third and fourth pharyngeal pouch syndrome><thymic and parathyroid agenesis syndrome><trend><undergrad><undergraduate><undergraduate student><velo-cardio-facial syndrome><velocardiofacial syndrome><velofacial hypoplasia>