ZFIN ID: ZDB-PUB-151009-4
Glucagon receptor inactivation leads to α-cell hyperplasia in zebrafish
Li, M., Dean, E.D., Zhao, L., Nicholson, W.E., Powers, A.C., Chen, W.
Date: 2015
Source: The Journal of endocrinology   227: 93-103 (Journal)
Registered Authors: Chen, Wenbiao, Li, Mingyu
Keywords: cell growth control, fish, glucagon, mutations, whole animal physiology
MeSH Terms:
  • Animals
  • Animals, Genetically Modified
  • Cell Proliferation/genetics
  • Cloning, Molecular
  • Embryo, Nonmammalian
  • Gene Expression Regulation, Developmental
  • Gene Silencing*
  • Glucagon-Secreting Cells/metabolism
  • Glucagon-Secreting Cells/pathology*
  • Hyperplasia/genetics
  • Receptors, Glucagon/genetics*
  • Receptors, Glucagon/metabolism
  • Zebrafish
PubMed: 26446275 Full text @ J. Endocrinol.
Glucagon antagonism is a potential treatment for diabetes. One potential side effect is α-cell hyperplasia, which has been noted in several approaches to antagonize glucagon action. To investigate the molecular mechanism of the α-cell hyperplasia and to identify the responsible factor, we created a zebrafish model in which glucagon receptor (gcgr) signaling has been interrupted. The genetically and chemically tractable zebrafish, which provides a robust discovery platform, has two gcgr genes (gcgra and gcgrb) in its genome. Sequence, phylogenetic, and synteny analyses suggest that these are co-orthologs of the human GCGR. Similar to its mammalian counterparts, gcgra and gcgrb are mainly expressed in the liver. We inactivated the zebrafish gcgra and gcgrb using transcription activator-like effector nuclease (TALEN) first individually and then both genes, and assessed the number of α-cells using an α-cell reporter line, Tg(gcga:GFP). Compared to WT fish at 7 days postfertilization, there were more α-cells in gcgra-/-, gcgrb-/-, and gcgra-/-;gcgrb-/- fish and there was an increased rate of α-cell proliferation in the gcgra-/-;gcgrb-/- fish. Glucagon levels were higher but free glucose levels were lower in gcgra-/-, gcgrb-/-, and gcgra-/-;gcgrb-/- fish, similar to Gcgr-/- mice. These results indicate that the compensatory α-cell hyperplasia in response to interruption of glucagon signaling is conserved in zebrafish. The robust α-cell hyperplasia in gcgra-/-;gcgrb-/- larvae provides a platform to screen for chemical and genetic suppressors, and ultimately to identify the stimulus of α-cell hyperplasia and its signaling mechanism.