THE ROLE OF ATROPHIN-2 IN CARTILAGE PATTERNING AND POLARITY IN ZEBRAFISH

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DESCRIPTION (provided by applicant): To diagnose and treat skeletal defects in humans, it is important to know the molecular pathways that initiate cartilage condensation, maturation and reorganization at joints during development. The early cartilaginous skeleton in the embryo serves as a blueprint for much of the bony skeleton of the adult, including the shapes and interconnections of different elements. We are using the genetic advantages of the zebrafish to identify genes essential for development of the craniofacial skeleton. Craniofacial cartilages and bones form from neural crest (NC) cells, unlike the vertebral or limb skeletons. In the pharyngeal skeleton in particular, NC cells acquire a dorsal-ventral (D-V) polarity, forming upper and lower jaws attached to the skull by joints. Even at this stage, each cartilage has a distinct polarity. In spite of the fundamental importance of cartilage patterning in vertebrate development and disease, surprisingly little is known about its underlying molecular control. Research has focused on mechanisms of cartilage maturation and replacement by bone in the limbs, but less is known about how cartilage elements acquire their identities, or how chondrocytes organize within an element to determine its shape. In the vertebrate jaw, a network of signals including Endothelin-1 (Edn1) has been implicated in D-V cartilage patterning. Our recent discovery of a zebrafish mutation in the transcription factor Atrophin-2 (Atr2), with joint defects similar to Edn1 mutants, provides the first opportunity to study the roles of Atr2 in regulating the mandibular signaling network. In addition, Atr2 mutants develop defects in cartilage stacking that suggest a possible function in planar cell polarity (PCP), which controls tissue polarity in many contexts but has not been shown to play a role in skeletal tissues. The long-term goal of this research is to understand the cellular and molecular basis of cartilage cell fate determination and polarity in the craniofacial skeleton. Aims 1 and 2 will test the hypothesis that cartilages and joints form as a result of a unique combination of Atr2-dependent signals (e.g. Edn1, Bmp, Fgf) from surrounding tissues that determine their fates. Aim 3 will test the hypothesis that Atr2 also regulates interactions between skeletal progenitors that control cell polarity, possibly through a novel PCP-dependent mechanism. These processes are likely to persist in the adult skeleton, and to be altered in human malformations and diseases of the skeleton.