LAUSR

Ciliopathies are rare genetic disorders characterized by dysfunction in primary cilia. Two ciliopathies, Alstrom Syndrome and Bardet-Biedl Syndrome (BBS), are characterized by high rates of obesity. However, they have strikingly different rates of diabetes. The rate is much higher in Alstrom patients relative to BBS. To gain insight into genetic mechanisms for this discrepancy we performed whole transcriptome sequencing on zebrafish depleted of the Alstrom gene, alms1, or the BBS gene, bbs1. We identified gene expression changes and found 8 genes that were differentially expressed in opposite directions between the two models. Among these, several exocrine pancreas enzymes were downregulated in Alstrom and/or upregulated in BBS. Based on this, and our previous demonstration of β-cell mass changes in models of both disorders, we hypothesized that the expression of exocrine pancreas enzymes affects endocrine pancreas function. This might suggest that impaired β-cell function in Alstrom results from reduced expression of exocrine pancreas enzymes, while the opposite may be true in BBS. These findings also support a non-ciliary role for BBS and Alstrom genes as we found them to be expressed in the non-ciliated acinar cells. To test our hypothesis, we overexpressed each enzyme in transgenic zebrafish embryos, in which β-cells can be visualized. In control animals, overexpression of the exocrine pancreas enzymes significantly increased the number of β-cells, suggesting that these enzymes play a role in regulating β-cell mass and function. Overexpression could also rescue the loss of β-cells observed in animals depleted of alms1. We have also found that the inactive form of these enzymes are selectively taken up by β-cells in vitro and induce proliferation in cultured MIN6 β-cells. This suggests a direct interaction between the exocrine and endocrine pancreas. Taken together, these data support the possibility that exocrine pancreatic enzymes may play an important role in the modulation of β-cells in diabetes. Disclosure T.L. Hostelley: None. J. Dunleavey: None. N.A. Zaghloul: None.