Increased GFAP gene expression is a common feature of CNS injury, resulting in its use as a reporter to investigate mechanisms producing gliosis. AP-1 transcription factors are among those proposed to participate in mediating the reactive response. Prior studies found a consensus AP-1 binding site in the GFAP promoter to be essential for activity of reporter constructs transfected into cultured cells, but to have little to no effect on basal transgene expression in mice. Since cultured astrocytes display some properties of reactive astrocytes, these findings suggested that AP-1 transcription factors are critical for the upregulation of GFAP in injury, but not for its resting level of expression. We have examined this possibility by comparing the injury response in mice of lacZ transgenes driven by human GFAP promoters that contain the wild-type AP-1 binding site to those in which the site is mutated. An intact AP-1 site was found critical for a GFAP promoter response to the three different injury models used: physical trauma produced by cryoinjury, seizures produced by kainic acid, and chronic gliosis produced in an Alexander disease model. An unexpected additional finding was that the responses of the lacZ transgenes driven by the wild-type promoters were substantially less than that of the endogenous mouse GFAP gene. This suggests that the GFAP gene has previously unrecognized injury-responsive elements that reside further upstream of the transcription start site than the 2.2 kb present in the GFAP promoter segments used here.
Keywords: Alexander disease; RRID:IMSR_JAX:003487; RRID:IMSR_TAC:fvb; STAT3 transcription factor; aging; brain injuries; cold injury; female; genetic; glial fibrillary acidic protein; gliosis; kainic acid; mice; seizures; sex characteristics; transcription; transcription factor AP-1; transgenic.
© 2018 Wiley Periodicals, Inc.
Conflict of interest statement
CONFLICTS OF INTEREST
The authors declare no conflicts of interest.
Astrocyte heterogeneity revealed by expression of a GFAP-LacZ transgene.Glia. 2006 May;53(7):677-87. doi: 10.1002/glia.20320. Glia. 2006. PMID: 16482522
Glial fibrillary acidic protein transcription responses to transforming growth factor-beta1 and interleukin-1beta are mediated by a nuclear factor-1-like site in the near-upstream promoter.J Neurochem. 1999 Apr;72(4):1353-61. doi: 10.1046/j.1471-4159.1999.721353.x. J Neurochem. 1999. PMID: 10098836
Transgenic analysis of GFAP promoter elements.Glia. 2013 Sep;61(9):1488-99. doi: 10.1002/glia.22536. Epub 2013 Jul 8. Glia. 2013. PMID: 23832770 Free PMC article.
Structure and transcriptional regulation of the GFAP gene.Brain Pathol. 1994 Jul;4(3):245-57. doi: 10.1111/j.1750-3639.1994.tb00840.x. Brain Pathol. 1994. PMID: 7952266 Review.
GFAP gene expression during development of astrocyte.Dev Neurosci. 1997;19(1):49-57. doi: 10.1159/000111185. Dev Neurosci. 1997. PMID: 9078433 Review.
Cited by 1 article
Organotypic slice culture based on in ovo electroporation for chicken embryonic central nervous system.J Cell Mol Med. 2019 Mar;23(3):1813-1826. doi: 10.1111/jcmm.14080. Epub 2018 Dec 18. J Cell Mol Med. 2019. PMID: 30565384 Free PMC article.