Role and Regulation of Cellular Polarity in Craniofacial Skeletogenesis

University Of California-Irvine, Irvine CA

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Abstract

Project Summary 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. Evidence 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 many laboratories now demonstrate that Dlx transcription factors regulate planar cell polarity signaling, well known for its critical roles in long bone growth plates, as well as craniofacial cartilage polarity in zebrafish. Embryos deficient in Dlx5 and Dlx6 show defects in cartilage stacking, like mutants in Wnt5b and Ror2. 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 previously funded work to address the hypothesis that Dlx5/6 directly regulate pharyngeal arch patterning and growth zone formation via planar cell polarity. Cartilage phenotypes will be evaluated in embryos and larvae in which Dlx5/6 have been genetically deleted and identify the polarity pathways regulated by Dlx5/6 as well as the signaling and responding cells. Aim 2 will address the functions of Wnt5- as well as Fat3-mediated planar polarity in early arch morphogenesis as well as later growth zones, including both transcriptional and non- transcriptional modes of propagation such as cytosplasmic extensions called cytonemes. New transgenic tools will allow tracking of polarity and visualization of cytonemes. Finally, Aim 3 will continue “evo-devo” projects focused on 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 the vertebrate skeleton. This work will lead to insights into the causes of human skeletal disorders of Dlx5/6, such as Split Hand Foot syndrome, as well as polarity disorders such as Robinow and Van Maldergem syndromes.