Illuminating the mechanisms that generate pattern and shape during growth and regeneration of the zebrafish fin

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PROJECT SUMMARY/ABSTRACT Tissues in a developing (or regenerating) appendage must correctly interpret their location in biological space, and use this positional information to inform size, pattern and shape during outgrowth. Relative changes in how cells interpret their positions during development can lead to debilitating changes in appendage phenotype, including limb malformations. Further, the ability to regenerate requires that tissues remember or reinterpret positional identity, then re-deploy this information to guide regrowth. Nonetheless, despite incredible relevance to both basic biology and biomedicine, it remains poorly understood how spatial context regulates the local morphogenetic processes which sculpt the pattern and shape of growing organs. Understanding the nature of positional identity in vertebrate appendages can further efforts to prevent, diagnose and treat congenital limb disorders, and will be necessary for development of advanced regenerative therapies. Zebrafish fins are a powerful system for studying mechanisms of growth and regeneration, and the caudal (tail) fin possesses an elegant, simple-yet-informative structure. After amputation or removal of any portion of the organ, fins regenerate rapidly to reproduce the original size, patterning and shape. Long- and short-finned mu- tants have served as crucial tools in decades of important progress towards the mechanisms regulating rela- tive fin size. Fin length phenotypes preserve the proportional patterning and overall shape of the fin structure— length is the only aspect of morphology that is altered. Indeed, before now, there have not been experimental models to disrupt fin ray patterning or the forked shape of the fin, and this lack of experimental tools means that essentially nothing is known about how pattern and shape are established or remembered. In this proposal, researchers introduce novel phenotypes in which patterning and shape are decoupled from size in the fin; these tools will be used to identify pathways and cellular processes underlying positional identity and the morphogenesis of form. The team will initially focus on mechanisms of skeletal patterning along the proximo-distal axis of fin rays, using the discovery that thyroid hormone regulates relative ray polarity. The re- searchers next ask how identity is imprinted across the medio-lateral axis. The team has developed a system in which the adult fin never develops a central cleft, and grows into a triangular rather than a forked shape. This phenotype will be used to test a model in which larval Shh expression regulates relative morphogenetic behaviors across the fin fold to pre-pattern the eventual forked shape of the organ. Researchers will explicitly identify the cell states that constitute modules of positional identity regulating size, patterning and shape—the three essential characteristics of overall fin morphology. In all, the proposed research will open fresh horizons for the broader field, leveraging new paradigms by which different aspects of positional identity can inform morphogenesis. These advances are expected to contribute foundational knowledge relevant in developing clinical interventions for congenital disorders, and critical in laying the groundwork for regenerative medicine.