|Keywords:||Bicaudal C1; RNA-binding protein; embryo; pancreas; endocrine progenitors; endocrine cells; MODY; Cysts|
|Full text PDF:||http://infoscience.epfl.ch/record/208771|
Mutations in Bicaudal C1 (BICC1), an RNA binding protein involved in translational regulation, have been associated with cystic kidney disease both in humans and in mice. Since kidney cysts associate with pancreatic defects in several human syndromes, we investigated the function of BICC1 in pancreas development. We found that pancreatic expression of BICC1 was restricted to the bipotent progenitors from E12.5 and later to the ducts. Deletion of Bicc1 caused pancreatic cysts, starting with duct dilation at E14.5. Around birth, ductal cells were hyperproliferative. However, the mitotic index was not increased at E14.5, arguing that the proliferation is not the cause of cyst formation. The expression of PKD2, which is mutated in 15% of the patients with autosomal polycystic kidney disease, was downregulated already before ducts start to enlarge, consistent with a role downstream of BICC1 that has been reported in kidney and in osteoblasts. Conversely, two other targets of BICC1 in kidneys, ADCY6 and PKIA, were not affected by Bicc1 deletion in E15.5 pancreata. In addition, after E14.5, but still before birth, Bicc1 deletion led to a decrease in the number of endocrine cells. Only half of the normal numbers of beta, delta, PP, and epsilon cells were present in Bicc1 KO pancreata. Alpha cells were reduced by 20%. Neither proliferation nor survival of the endocrine cells was affected in Bicc1 KO pancreata. Instead, we observed in Bicc1 KOs a reduction of the production of endocrine progenitor cells expressing NEUROG3+, a major regulator of endocrine cell differentiation. Bicc1 deletion reduced the activity of Neurog3 promoter. Therefore, direct translation regulation of Neurog3 by BICC1 can be ruled out. However, the transcriptional activators of Neurog3 promoter, HNF1B, ONECUT1, PDX1, FOXA2, SOX9 and its transcriptional repressor, HES1, were unaffected by Bicc1 deletion, arguing that they unlikely mediate BICC1 regulation of NEUROG3+ cell production. Finally, new BICC1 variants have been uncovered in patients with cystic kidneys, and the two oldest diabetes. Contrary to what has been observed with previously reported mutations, the variants did not affect the ability of BICC1 to inhibit canonical WNT signaling. In conclusion, this study showed that BICC1 is important to maintain duct homeostasis and endocrine progenitor production. BICC1 may thus be a susceptibility factor for diabetes when it is mutated.