Adult teleost fish and urodele amphibians have the capacity to regenerate entire amputated appendages. By contrast, regenerative healing of mammalian limbs is limited to digit tips. During limb regeneration in urodeles and fin regeneration in teleosts, regeneration is precisely regulated such that only the appropriate structures are replaced. One of the major unexplained questions of appendage regeneration is how adult cells in the injured area retain or recognize the positional information necessary to accomplish this. In the teleost fin, a complex organ containing bone, connective tissue, epidermis, blood vessels, nerves, and pigment cells, positional information appears to be encoded in part by a gradient in the rate of regeneration along the proximodistal (PD) axis. That is, proximal structures regenerate much more quickly than distal structures. The differences in underlying regulation are currently unexplained at the cellular and molecular levels. However, based on our published results and new data, it is likely that signaling by Fgfs through the Erk pathway is an important contributor. Here, we propose to dissect regulatory mechanisms of regenerative growth rate in the zebrafish caudal fin. We hypothesize that, graded molecular regulatory programs underlie graded differences in anatomy and cellular proliferation along the PD axis of the regenerating fin. To test this hypothesis, we propose 3 Specific Aims. 1) We will define PD gradients of regenerative rate, cellular proliferation, blastemal length, and Fgf signaling activity. 2) We will define the mechanism by which Fgf signaling encodes the regenerative rate. Here, we will examine how experimental manipulation of Fgf and Erk signaling activity affect regenerative rate, using new transgenic lines that facilitate inducible augmentation, or reduction, of signaling through these pathways. 3) Using one of these transgenic lines, a strain that facilitates inducible expression of a dominant-negative Fgf receptor, we will perform a genetic screen for mutations that suppress the requirement for Fgf signaling during fin regeneration. We will classify the different mutants found in this screen with the goal of identifying the disrupted genes. Our molecular genetic approach to the regulation of regenerative rate in zebrafish appendages will provide a foundation for understanding important regulatory mechanisms active during regenerative organogenesis, and may also facilitate regenerative therapies for a variety of human degenerative diseases.
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