βA3/A1-crystallin is a critical mediator of STAT3 signaling in optic nerve astrocytes

Sci Rep. 2015 Mar 4:5:8755. doi: 10.1038/srep08755.

Abstract

We have previously reported that in the Nuc1 rat, which has a spontaneous mutation in Cryba1 (the gene encoding βA3/A1-crystallin), astrocytes exhibit decreased Notch signaling, leading to reduced promoter activity for glial fibrillary acidic protein (GFAP). Interestingly, in both Nuc1 astrocytes and in wild type astrocytes following knockdown of Cryba1, vascular endothelial growth factor (VEGF) secretion is decreased. This has led us to explore signaling mediators that could be regulated by βA3/A1-crystallin to modulate both GFAP and VEGF. Several studies have shown that the signal transducer and activator of transcription 3 (STAT3) is involved in the co-regulation of GFAP and VEGF. We show that STAT3 and βA3/A1-crystallin may co-regulate each other in astrocytes. Such co-regulation would create a positive feedback circuit; i.e., in the cytosol of astrocytes, βA3/A1-crystallin is necessary for the phosphorylation of STAT3, which then dimerizes and translocates to the nucleus to form DNA-binding complexes, activating transcription of Cryba1. This stoichiometric co-regulation of STAT3 and Cryba1 could potentiate expression of GFAP and secretion of VEGF, both of which are essential for maintaining astrocyte and blood vessel homeostasis in the retina. Consistent with this idea, Cryba1 knockout mice exhibit an abnormal astrocyte pattern and defective remodeling of retinal vessels.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Astrocytes / metabolism*
  • Base Sequence
  • Binding Sites / genetics
  • Crystallins / genetics
  • Crystallins / metabolism*
  • Gene Expression
  • Immunoblotting
  • Mice, Knockout
  • Microscopy, Confocal
  • Molecular Sequence Data
  • Mutation
  • Optic Nerve / cytology
  • Optic Nerve / metabolism*
  • Phosphorylation
  • Promoter Regions, Genetic / genetics
  • Rats
  • Receptors, Notch / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • STAT3 Transcription Factor / metabolism*
  • Signal Transduction*
  • beta-Crystallin A Chain

Substances

  • Cryba1 protein, mouse
  • Crystallins
  • Receptors, Notch
  • STAT3 Transcription Factor
  • beta-Crystallin A Chain
  • betaA3-crystallin, rat