The processes of bone formation, shared by all vertebrates, are often affected in human skeletal dysplasias, resulting in significant defects to craniofacial skeletogenesis. The skull is formed from endochondral bones, which develop through mineralization of cartilage, and intramembranous bones, which develop directly from condensed mesenchymal cells. Defects in the processes of chondrogenesis and/or osteogenesis lead to craniofacial defects and skeletal dysplasias, and many of the genes responsible for these skeletal malformations remain unknown. Although the skulls of fish and humans are distinctly different, many of the skeletal elements are homologous and the genes required to form these structures are conserved. Therefore, zebrafish mutants displaying skeletal dysmorphologies provide an ideal system to study human craniofacial skeletogenesis and skeletal dysplasias. Our laboratory has identified a spontaneous mutant, referred to as koliber (kol), which displays a late onset skeletal phenotype. Bone and cartilage staining show defects consisting of hyperossified bone, as well as cartilage loss and bone fusion in the growth plates of the craniofacial skeleton. Using positional cloning, we have narrowed down the kol critical region to Chromosome 1 and identified a candidate gene. Interestingly, this region of the zebrafish genome shares genomic synteny with mammals;no gene within this critical region has previously been implicated in zebrafish bone development, suggesting the kol mutation may provide novel insight into craniofacial skeletogenesis. This proposal aims to characterize the kol mutant, confirm the kol mutation and determine the signaling pathways affected by the kol mutation. Techniques involving the use of bone and cartilage staining, genome editing and transgenic reporter lines will be used to compare the processes of skull formation in normal and mutant fish. Most mutations previously identified in zebrafish and mice affect genes vital to early stages of craniofacial skeletal development, while genes involved in later stages have largely been unstudied. Discovery of a novel gene or pathway necessary to juvenile vertebrate bone formation will provide significant insight into problems of pediatric craniofacial skeletal development. The kol mutant may shed new light on this considerably unstudied area of bone development.

Public Health Relevance

This project focuses on abnormal bone development, specifically irregular skull formation which is a relatively frequent cause of birth defects. The identification of a mutation causing bone development defects in zebrafish will shed new light on the process of human skeletal formation and aid in the possible understanding of skeletal birth defects.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
Predoctoral Individual National Research Service Award (F31)
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NIDR Special Grants Review Committee (DSR)
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Frieden, Leslie A
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Children's Memorial Hospital (Chicago)
United States
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