Genetic and cellular analysis of zebrafish fin development.

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My research program involves the comparative analysis of fin and limb development, and the molecular mechanisms that may have contributed to the evolution of tetrapod limbs from paired fins (pectoral, pelvic). During early development, the early pectoral fin bud shows a lot of similarity with the limb bud but fin development quickly diverges starting with: 1) the formation of a fin fold; 2) migration of mesenchymal cells in the fold; 3) formation of actinotrichia, rigid fibers that act as a scaffold for mesenchymal cell migration and as a skeletal support for the growing fin fold. These migrating mesenchymal cells (named hereafter MMCs) play a fundamental role in the formation of the larval fin and the fin rays, however their exact role is not fully understood. Such MMCs are not present in developing limb buds suggesting that these cells have been lost or contribute to different tissues in tetrapod species. We recently characterized two gene regulatory regions, 2Pepi and m-Inta11 that are active in MMCs arising at the onset of fin fold formation in zebrafish embryonic fins. 2Pepi is responsible for actinodin 1 (and1) expression in a population of MMCs. And1 is a fish-specific gene that encodes for structural components of actinotrichia; the and gene family has been lost from the tetrapod genomes during evolution. In another study, we also showed that ablation of the m-Inta11 expressing MMCs impairs early fin development. We think MMC migration and function depends on the proper formation and maintenance of actinotrichia. We propose both of these processes are mediated by the expression of 5'hoxa/hoxd genes.In the coming five years, my research program will integrate data and reagents from our previous work to investigate the role of MMCs and their relationship to the actinotrichia to better understand their contribution to fin development. This project will allow us to better understand fin development and provide a better insight into the fin-to-limb transition. More specifically, I propose the following 4 aims:1) to use a cell lineage tracing approach to determine the fate of specific subsets of MMCs. 2) to investigate the long-term effects of the ablation of the and1-expressing MMCs on fin development. 3) to examine the effects of the genetic disruption of actinotrichia formation on MMCs and resulting consequences on fin development. 4) to examine the 5'hoxa/hoxd regulation of and1 mesenchymal expression. Investigating the role and fate of the MMCs, including their contributions to actinotrichia, fin fold, and ray development gives us an opportunity to better understand the mechanisms of fin development and provides a better insight into morphological changes underlying the fin-to-limb transition. In addition, understanding the regulatory link between and1 and 5'HoxA/D proteins could shed light on how regulatory changes contributed to the loss of the actinodin genes from the tetrapod genome.