Different mechanisms regulate expression of zebrafish myelin protein zero (P0) in myelinating oligodendrocytes and its induction following axonal injury

J Biol Chem. 2014 Aug 29;289(35):24114-28. doi: 10.1074/jbc.M113.545426. Epub 2014 Jul 15.

Abstract

Zebrafish CNS axons regenerate robustly following injury; it is thought that CNS oligodendrocytes contribute to this response by expressing growth-promoting molecules. We characterized the mpz gene, which encodes myelin protein zero and is up-regulated in oligodendroglia following axonal injury. The 2.5-kb mpz mRNA is expressed from a single TATA box promoter. Four independent Tg(mpz:egfp) transgenic zebrafish lines, in which GFP was expressed under the mpz promoter and 10 kb of genomic 5'-flanking sequence, showed transgene expression in CNS oligodendrocytes from larval development through adulthood. Following optic nerve crush injury, the mpz:egfp transgene was strongly up-regulated in oligodendrocytes along the regenerating retinotectal projection, mirroring up-regulation of endogenous mpz mRNA. GFP-expressing oligodendroglia were significantly more abundant in the regenerating optic pathway, resulting from both transgene induction in oligodendroglial precursors and the birth of new cells. Up-regulation of the mpz:egfp transgene was not dependent on axonal regeneration, suggesting that the primary signal may be axonal loss, debris, or microglial infiltration. Deletion experiments indicated that an oligodendroglial enhancer located in the region from -6 to -10 kb with respect to the mpz transcriptional start site is dissociable from the cis-regulatory element mediating the mpz transcriptional response to axonal injury, which is located between -1 and -4 kb. These data show that different mechanisms regulate expression of zebrafish mpz in myelinating oligodendrocytes and its induction following axonal injury. The underlying molecular events could potentially be exploited to enhance axonal repair following mammalian CNS injury. The transgenic lines and cis-regulatory constructs reported here will facilitate identification of the relevant signaling pathways.

Keywords: Axon; Myelin; Oligodendrocyte; Protein Zero; Regenerative Medicine; Transcription Regulation; Zebrafish.

Publication types

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

MeSH terms

  • Animals
  • Axons*
  • Base Sequence
  • DNA Primers
  • Green Fluorescent Proteins / genetics
  • In Situ Hybridization
  • Myelin P0 Protein / genetics
  • Myelin P0 Protein / metabolism*
  • Oligodendroglia / cytology
  • Oligodendroglia / metabolism*
  • Promoter Regions, Genetic
  • Transgenes
  • Zebrafish / metabolism*

Substances

  • DNA Primers
  • Myelin P0 Protein
  • Green Fluorescent Proteins