Toward discovery of novel key genes for pancreatic beta cell regeneration in zebrafish

Diabetes is becoming a leading health issue worldwide. It occurs under insulin resistance/deficiency and when insulin-producing pancreatic beta-cell mass is dramatically reduced. Besides therapeutic strategies to preserve beta-cell mass and function and improve insulin treatments, beta-cell replacement constitutes a promising alternative to replenish the pancreas with functional beta-cells. Several observations of pancreatic cell plasticity has led to the hope that triggering beta-cell regeneration within the pancreas could be harnessed in future therapies. Still, mammals show limited regenerative capabilities, making difficult the study of these mechanisms. In contrast, zebrafish is extensively used for regeneration studies notably of beta-cells.
We recently showed that the adult zebrafish ducts display characteristics of embryonic pancreatic progenitors that can give rise to beta-cells in physiological and induced diabetic condition*, and we determined the transcriptomic profile of zebrafish pancreatic ducts during beta-cell regeneration. To identify new genes crucial for beta-cell regeneration we plan to investigate the role of about 10 selected candidate genes by analyzing invalidating mutations created by CRISPR/Cas9. Their effect on beta-cell regeneration will be studied in 7-20 old larvae which we have established as experimental platform for functional studies. This project should help decipher the molecular mechanism of beta-cell regeneration.