Vhnf1 acts downstream of Bmp, Fgf, and RA signals to regulate endocrine beta cell development in zebrafish.
Bmp, Fgf, and retinoic acid (RA) signals have been implicated as regulators of pancreas development. However, the integration of these signaling pathways in vivo is not fully understood. Variant hnf1 (Vhnf1) is a transcription factor involved in pancreas, liver, and kidney development and its mutation in zebrafish causes underdeveloped pancreas and liver. We investigated the signaling pathways that regulate vhnf1 expression during pancreas development. First, we showed that Bmp activity is required for vhnf1 expression in the endoderm. In chordin (a Bmp antagonist) morpholino (MO)-injected embryos, vhnf1 expression in endoderm and in endocrine beta cells is expanded. On the other hand, in alk8 (a type I TGFbeta receptor) MO-injected embryos, vhnf1 expression in the endoderm is significantly reduced. Second, we showed that Fgf signaling participates in regulation of pancreas development through the vhnf1 pathway. Third, we demonstrated that RA fails to rescue reduction of insulin expression in vhnf1 mutants, whereas overexpression of vhnf1 restores insulin expression that is repressed by treatment with a RA receptor inhibitor. And finally, we revealed that both Bmp and Fgf signals act genetically upstream of RA in directing pancreas development. Taken together, our data establish that vhnf1 acts downstream of the signaling pathways of RA, Bmp, and Fgf to regulate pancreas development in zebrafish.
Song
Jianbo
J
Department of Molecular, Cell and Developmental Biology, University of California-Los Angeles, CA 90095, USA.
Kim
Hyon J
HJ
Gong
Zhiyuan
Z
Liu
Ning-Ai
NA
Lin
Shuo
S
D000818:Animals; D001483:Base Sequence; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism*; D004843:Epistasis, Genetic; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D051539:Hepatocyte Nuclear Factor 1-beta / Q000235:genetics / Q000378:metabolism*; D007328:Insulin / Q000235:genetics / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D008954:Models, Biological; D020319:Oligodeoxyribonucleotides, Antisense / Q000235:genetics; D017354:Point Mutation; D015398:Signal Transduction; D014212:Tretinoin / Q000378:metabolism* / Q000494:pharmacology; D015027:Zebrafish / Q000196:embryology* / Q000235:genetics / Q000378:metabolism*; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*
D019485:Bone Morphogenetic Proteins; D007328:Insulin; D020319:Oligodeoxyribonucleotides, Antisense; D029961:Zebrafish Proteins; C496498:hnf1ba protein, zebrafish; D051539:Hepatocyte Nuclear Factor 1-beta; D014212:Tretinoin; D005346:Fibroblast Growth Factors