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4 Rapunzel, A Novel Zebrafish Mutant with Loss of Nutrition-Dependent Growth Control

Background and Purpose of Study: The essential genetics of normal human growth are not well understood. Size and form are maintained through the appropriate coordination of isometric and allometric growth. In addition, humans must be able to adapt their nascent developmental programs, such as growth, to ever changing environmental conditions, including nutritional status. When isometric or allometric control of growth is lost, disorders of growth control including overgrowth, undergrowth and cancer ensue. We use zebrafish and in particular, the zebrafish fin, as a genetically and physiologically tractable model to dissect the biology of growth control. Growth of the adult zebrafish caudal fin is episodic and isometric. In addition, when adult zebrafish are fasted, checkpoints rapidly abrogate caudal fin growth.Methods and Summary of Results: An ENU-based forward mutagenesis screen identified the fin overgrowth mutant rapunzel. We used a positional cloning strategy to map the rapunzel mutation to a narrow critical region on zebrafish chromosome 16 containing 4 novel transcripts (wz750, wz17566, wz7309 and wz2605). 5′ and 3′ RACE were used to clone full-length cDNA's for these candidate genes, one of which contains a novel missense mutation. We are using in situ hybridization, zebrafish transgenesis, cell culture and morpholino knockdown to interrogate this genetic lesion further. Morphometric analysis reveals that fin growth in rapunzel is continuous and allometric, leading to overgrowth of all fins. Interestingly, when rapunzel mutants were fasted for 30 days, they added ∼7 caudal fin ray segments (7.2 ± 2). This is in contrast to both wild type zebrafish (0 ± 1) and the long fin mutant (data not shown), both of which terminated fin ray growth rapidly upon fasting. Finally, we used blastula transplantation to explore the cell/tissue autonomy of the rapunzel mutation. Analysis of rapunzel chimeras revealed a critical role of the fin ray endothelium in generating overgrowth in rapunzel mutants.Conclusions: Forward genetics identifies rapunzel, a fin overgrowth mutant wherein episodic and isometric control of fin growth is lost. Physiologically, rapunzel bypasses checkpoints that normally serve to abrogate growth when nutritional conditions are poor, moreover this property appears autonomous to the fin ray endothelium. Positional cloning has mapped rapunzel to a narrow critical region containing 4 novel transcripts. Progress on cloning the rapunzel mutation will be presented.