Role of the Bradykinin Pathway in Craniofacial Development


Principal Investigator: LAURA ANNE JACOX
Abstract: DESCRIPTION (provided by applicant): The broad goal of this proposal is to define signaling pathways that direct craniofacial development, with the long-term goal of diagnosing and treating abnormalities. Specific focus is on the jaws, derived from the neural crest, and on the mouth. The mouth develops from the "extreme anterior domain" (EAD), where the ectoderm and endoderm directly juxtapose. The Bradykinin pathway, previously described only in adults, is locally necessary in the EAD, for mouth formation. However, this pathway also has more global effects on face formation. I hypothesize that the EAD is a craniofacial organizer that regulates mouth and cranial neural crest development, through graded Bradykinin signaling, and culminating in NO production. There are two Aims. Aim 1 will characterize the effects of CPN loss of function on neural crest formation. CPN is a Bradykinin pathway mediator, expressed in the EAD, and loss of function results in abnormal mouth and neural crest tissues. I hypothesize that CPN signaling regulates cranial neural crest determination and serves as a migration stop signal at the facial midline. These hypotheses will be tested after local loss of CPN function using antisense oligonucleotides and a face transplant assay developed in the Sive lab. The effect on neural crest migration will use lineage labeling with fluorescent, injected tracers. Aim will determine the role of Bradykinin signaling on mouth and neural crest formation. CPN processes the ligand Bradykinin to desArgBradykinin. Both are active ligands and lead to nitric oxide NO production. I hypothesize that Bradykinins act in a concentration-dependent manner, through the Bradykinin receptor, to determine the mouth and cranial neural crest. These hypotheses will be tested by implanting beads loaded with Bradykinin peptides into loss of function embryos, and analyzing correction of defects at different distances from the bead. The spectrum of tissues that can respond to Bradykinin signaling will be determined by analysis of Bradykinin receptor function. This study uses the frog Xenopus, an ideal model for analysis of craniofacial defects, as embryos develop outside the mother, and as the developing face is readily accessible. Hundreds of embryos can be obtained, and these allow rapid assays, since mouth and jaw precursors form 36 hours after fertilization, and are functional by 3 days. The large embryos allow micromanipulation, and gain and loss of function assays can be performed. Facial structure and regulatory genes appear conserved between Xenopus and mammals, suggesting that the information gained from this study will be directly relevant to human biology. Craniofacial anomalies are prevalent, appearing in 1 out of 700 live births, yet most have unknown cause. This project is exciting since Bradykinin signaling in facial development has not previously been described, neither has the role of the EAD as a facial organizer. These studies interface with the NIDCR mission, and have potential to provide etiologies for craniofacial defects and suggest future early, minimally invasive treatments.
Funding Period: 2012-09-01 - 2017-08-31
more information: NIH RePORT

Detail Information

Research Grants30

  1. Genetic and Morphometric Analysis of Facial Clefts
    REBECCA MICHELLE GREEN; Fiscal Year: 2013
    ..Based on this data, we hope be able to build out how this pathway is interacting with other established facial development pathways to determine the overall facial gene regulatory network for facial development. ..
  2. Eph/ephrin signaling in craniofacial development and disease
    JEFFREY OHMANN BUSH; Fiscal Year: 2013
    ..abstract_text> ..
  3. Building a Gene Regulatory Network for prdm1a During Zebrafish Craniofacial Devel
    KRISTI A LAMONICA; Fiscal Year: 2013
    ..abstract_text> ..
  4. Characterizing the mechanisms of PDGFRalpha regulation in upper lip development
    Fenglei He; Fiscal Year: 2013
    ..This study will benefit treatment and prevention of cleft lip in the future, to ultimately reduce the occurrence of this birth defect in newborns. ..
  5. Proteolysis of cadherins in cranial neural crest
    ..In the long term, our results will facilitate the development of novel screening, diagnosis, and treatment modalities and/or illuminate new therapeutic targets to combat aberrant EMT-associated human diseases, syndromes and cancers. ..
  6. Characterization of neural crest gene expression using a new transgenic Xenopus m
    Shuo Wei; Fiscal Year: 2013
    ..The successful achievement of these outcomes will provide us new tools and knowledge in craniofacial research. ..
  7. The role of PHD12 in epigenetic control of cranial neural crest EMT
    Pablo Hernan Strobl Mazzulla; Fiscal Year: 2013
    ..Taking together we will systematically address the epigenetic role of PHD12 on NC EMT and it implication on the formation of craniofacial derivatives. ..
    Patricia K Donahoe; Fiscal Year: 2013
    ..Further, the methods devised for this study of CDH may have broader implications across other congenital anomalies. ..
    Steven M Anderson; Fiscal Year: 2013
    ..This concerted effort will provide mechanistic underpinnings for understanding lactation failure in women related to diabetes and/or obesity. ..
  10. The role of continuous phenotypic variation in structural defects of the face
    Ralph S Marcucio; Fiscal Year: 2013
    ..This basic research will help develop metrics for better in utero diagnostics and eventual treatments of structural birth defects of the face. ..
    Hazel L Sive; Fiscal Year: 2013
    ..This study will suggest why the primary mouth fails to form correctly in a human embryo, and help explain the molecular causes of craniofacial birth defects. ..
  12. A role for the methyltransferase NSD3 in neural crest specification and migration
    Bridget T Jacques-Fricke; Fiscal Year: 2013
    ..This project aims to determine how neural crest cells form and travel through the embryo, leading to new prevention and treatment options for neural crest-based disorders, such as cleft lip and palate. ..
  13. A Cis-regulatory Model for Neural Border Induction
    Daniel Meulemans Medeiros; Fiscal Year: 2013
    ..The proposed work will support the training of one postdoctoral scholar for two years. ..
  14. Function of Toll-Like Receptors Throughout Gestation
    GIL G MOR; Fiscal Year: 2013
  15. Ectodermal Placode Development into Sensory Structures
    Marianne Bronner; Fiscal Year: 2013
    ..Preliminary data suggest that knock-down of Pea3 in the olfactory territory up-regulates the neural crest marker, Sox10. We will test whether this and other factors may act as switch points between placodal versus neural crest fate. ..
  16. Genetic regulation of Inner and Middle Ear Development
    Andrew K Groves; Fiscal Year: 2013
    ..Our final aim focuses on the function the Foxi3 gene in the development of the middle ear. ..
  17. Craniofacial Development and Disease
    Paul A Trainor; Fiscal Year: 2013
    ..For the purpose of this proposal we focus on one gene, called Nr6a1, which appears to be critical for the neural crest cell formation process and as such is essential for normal craniofacial development. ..
  18. Human Genome Sructural Variation
    Evan Eichler; Fiscal Year: 2013
    ..abstract_text> ..
  19. Determining the molecular mechanism by which prdm1a regulates neural crest specif
    DAVALYN RENEE POWELL; Fiscal Year: 2013
    ..Using these experiments, I will be able to determine the mechanism by which prdm1a regulates neural crest specification through gene regulation. ..
  20. Role of actin cytoskeleton regulators in craniofacial development and disease
    Shuyi Nie; Fiscal Year: 2013
    ..3) Functionally characterize Cdc42ep1 and additional candidate genes identified in the microarray screen for their roles in neural crest development. 4) Determine functional and physical interactions between ACRs in CNC migration. ..