Wnt Signaling in Craniofacial Developmental Disorders

Project: Research project

Description

DESCRIPTION (provided by applicant): The long-term goal of our research is to uncover the molecular and genetic mechanisms of craniofacial birth defects in Wnt signaling mutant animal models in order to provide a basis for developing innovative prevention and therapeutic strategies. Congenital craniofacial defects, particularly the cleft lip with or without cleft palate (CLP), are among the most common birth defects in humans. CLP results from the failure of fusion in the lip or roof of the mouth during early embryonic development and has complex, but largely unknown, etiology. The canonical Wnt/ss-catenin pathway plays important roles in morphogenesis, and gene mutations in this pathway, are implicated in human genetic disease. However, the role of the canonical Wnt pathway in orofacial development, particularly in the lip and palate formation and fusion processes, remains poorly understood. We have recently found that canonical Wnt signaling is activated in the fusion sites of the orofacial primordia, and that CLP occurred in mice with a single gene mutation of Wnt signaling molecules. The mutants exhibit dramatic alterations in morphogenetic movements and candidate Wnt target genes in both facial ectoderm and mesenchyme. Therefore, we hypothesize that CLP is caused by disruption of Wnt/ss-catenin signaling pathway and its downstream targets in both facial ectoderm/epithelium and mesenchyme during lip/palate formation and fusion. Aim 1 will evaluate our hypothesis that conditional inactivation of canonical Wnt signaling in facial ectoderm will cause CLP. Aim 2 will address whether two Wnt signaling co-receptors are functional redundant for canonical Wnt signaling in development of face, particularly in the facial mesenchymal lineage cells. Our study will provide new insights into the pathogenesis and mechanisms of CLP. These in turn, may translate into an application to prevent and treat these common birth defects through manipulating Wnt signaling. PUBLIC HEALTH RELEVANCE: Congenital craniofacial defects such as cleft lip with or without cleft palate (CLP) are among the most common birth defects in humans with high prevalence and a poorly understood etiology. The current study is targeted to uncover the mechanisms of these congenital defects through genetic manipulation of the morphogenetic Wnt signaling pathway in mutant animal models, which may provide a basis for future translational applications.
StatusFinished
Effective start/end date4/1/113/31/16

Funding

  • National Institutes of Health: $385,000.00
  • National Institutes of Health: $369,600.00
  • National Institutes of Health: $384,688.00
  • National Institutes of Health: $383,438.00
  • National Institutes of Health: $385,000.00

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Cleft Palate
Ectoderm
Lip
Catenins
Palate
Mesoderm
Wnt Signaling Pathway
Cleft Lip
Genes
Mutation
Inborn Genetic Diseases
Medical Genetics
Animal Models
Morphogenesis
Embryonic Development
Mouth
Molecular Biology
Epithelium
Research

ASJC

  • Medicine(all)
  • Dentistry(all)