Our laboratory is interested in the role that Wnt/PCP signaling plays in the morphogenetic processes that are required for cartilage formation. We utilize the powerful and innovative combination of genetic, embryological, and molecular methods uniquely available for the teleost, Danio rerio, zebrafish to address this question. Two genes involved in the Wnt/PCP pathway that are of interest to us wnt 5b and glypican 4 (gpc4). Wnt5b is one of the key activators of the PCP pathway, while gpc4 is likely a Wnt co-receptor. Zebrafish mutant for wnt 5b and gpc4 have be identified and are observed with shorter body axis, attributed to wnt 5b and gpc4 requirement for proper convergance and extension movement during gastrulation, and craniofacial skeleton malformation. We find zebrafish mutant in either of these genes have craniofacial chondrocytes that are unable to intercalate properly and therefore do not form organized rod-like cartilage structures. The goal of our future experiments is to elucidate the developmental step(s) in which wnt 5b and glypican 4 are necessary for proper cartilage morphogenesis. We are also interested in recent work suggesting an interplay between Wnt/PCP signaling and primary cilia. Intriguingly, many of the characterized human ciliopathies have some form of cranial defect. A secondary goal of our work will be to determine if there is an interaction between primary cilia and Wnt/PCP signaling in cartilage formation. We will use our wnt 5b and glypican 4 mutant zebrafish to test for genetic interactions. Public Health Relevance: Approximately 1 in every 1000 live births in the United States present with some form of craniofacial defect, including cleft lip and cleft palate. Infants with cleft disorders are more susceptible to respiratory infections and suffer from difficulties in breathing, swallowing, and speaking, which require the child to have multiple corrective surgeries to be able to live a normal life. Many of the congenital craniofacial defects seen in the clinic are caused by the abnormal morphogenesis and migration of the progenitor cells that will form the cranial skeleton. By studying the conserved mechanisms that form the craniofacial skeleton in vertebrate animal models we will be able to improve the diagnosis, treatment and prevention of these common occurring pediatric malformations.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32DE019986-03
Application #
8113144
Study Section
NIDCR Special Grants Review Committee (DSR)
Program Officer
Frieden, Leslie A
Project Start
2009-09-01
Project End
2012-07-06
Budget Start
2011-09-01
Budget End
2012-07-06
Support Year
3
Fiscal Year
2011
Total Cost
$49,240
Indirect Cost
Name
Children's Memorial Hospital (Chicago)
Department
Type
DUNS #
074438755
City
Chicago
State
IL
Country
United States
Zip Code
60611
Sisson, Barbara E; Dale, Rodney M; Mui, Stephanie R et al. (2015) A role of glypican4 and wnt5b in chondrocyte stacking underlying craniofacial cartilage morphogenesis. Mech Dev 138 Pt 3:279-90
Dale, Rodney M; Topczewski, Jacek (2011) Identification of an evolutionarily conserved regulatory element of the zebrafish col2a1a gene. Dev Biol 357:518-31
Topczewski, Jacek; Dale, Rodney M; Sisson, Barbara E (2011) Planar cell polarity signaling in craniofacial development. Organogenesis 7:255-9