A functional skeletal system depends on the coordinated development of cartilages and bones during embryogenesis. However, little is known about the cellular and molecular mechanisms that control the polarized growth of cartilages, which determine endochondral bone size and shape. Unraveling the signals that direct mesenchymal cells to condense and align into pre-chondrogenic stacks is key to understanding early events that shape the organization and growth of the skeleton. Elucidating these processes will allow better diagnosis and treatments for skeletal malformations and birth defects. Moreover, molecules that control cartilage morphogenesis and differentiation may be of considerable clinical importance both for improvements in diagnosing and treating congenital birth defects as well as developing mesenchymal stem cell based therapies for skeletal disorders. Our recent finding that planar cell polarity pathways are essential for cartilage cells to stack properly, suggests a previously unappreciated mechanism for patterning cartilage growth plates of long bones as well as growth zones in bones of the skull. Dramatic results from our laboratory now demonstrate that Hedgehog signaling, well known for its critical roles in long bone growth plates, also regulates cartilage polarity in zebrafish. Embryos deficient in Hedgehog signaling show defects in cartilage stacking. Moreover, comparisons of cartilage growth zones in African cichlid fishes that have evolved dramatically different craniofacial bone shapes, reveal that growth zone size differences during larval development correlate with these species-specific shapes.
Aim 1 will build upon our previously funded work to address the hypothesis that Hedgehog signaling regulates growth zone patterning via planar cell polarity. Cartilage phenotypes will be evaluated in embryos and larvae in which Hedgehog signaling has been manipulated pharmacologically or genetically. We will identify the polarity pathways regulated by Hedgehog as well as the signaling and responding cells.
Aim 2 will address the functions of polarity in growth zones, including modes of propagation, responsiveness to Hedgehog, and roles in the perichondrium. For this we have new transgenics with which we can track polarity, and methods for targeting perichondrial cells. Finally, Aim 3 will focus on a new ?evo-devo? project in the lab, discovering new genes involved in cartilage polarity and growth zones using quantitative trait locus mapping in cichlids. Together, these studies will lead to mechanistic insights into the relatively unexplored functions of cellular polarity in endochondral bones of the vertebrate skeleton. This work will lead to insights into the causes of human skeletal disorders of Hedgehog signaling, such as brachydactyly, as well as polarity disorders such as Robinow and Van Maldergem syndromes.
The proposed studies will provide some of the first evidence that cartilage polarity influences skeletogenesis. Defining molecules that control cartilage development may be of clinical importance both for improving treatments for cartilage and joint injuries and in efforts to induce cartilage from stem cells. The Fat3 and Wnt5 signaling pathways are also implicated in birth defects, including Robinow syndrome, and understanding their functions could help improve diagnosis and treatments for this and related diseases.
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