Conditional ablation of the Mat1 subunit of TFIIH in Schwann cells provides evidence that Mat1 is not required for general transcription

J Cell Sci. 2002 Nov 15;115(Pt 22):4275-84. doi: 10.1242/jcs.00121.

Abstract

The mammalian Mat1 protein has been implicated in cell cycle regulation as part of the Cdk activating kinase (CAK), and in regulation of transcription as a subunit of transcription factor TFIIH. To address the role of Mat1 in vivo, we have used a Cre/loxP system to conditionally ablate Mat1 in adult mitotic and post-mitotic lineages. We found that the mitotic cells of the germ lineage died rapidly upon disruption of Mat1 indicating an absolute requirement of Mat1 in these cells. By contrast, post-mitotic myelinating Schwann cells were able to attain a mature myelinated phenotype in the absence of Mat1. Moreover, mutant animals did not show morphological or physiological signs of Schwann cell dysfunction into early adulthood. Beyond 3 months of age, however, myelinated Schwann cells in the sciatic nerves acquired a severe hypomyelinating morphology with alterations ranging from cells undergoing degeneration to completely denuded axons. This phenotype was coupled to extensive proliferation and remyelination that our evidence suggests was undertaken by the non-myelinated Schwann cell pool. These results indicate that Mat1 is not essential for the transcriptional program underlying the myelination of peripheral axons by Schwann cells and suggest that the function of Mat1 in RNA polymerase II-mediated transcription in these cells is regulatory rather than essential.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Division / genetics
  • Cell Lineage / genetics
  • Cyclin-Dependent Kinase-Activating Kinase
  • Cyclin-Dependent Kinases / deficiency*
  • Cyclin-Dependent Kinases / genetics
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Early Growth Response Protein 2
  • Female
  • Gene Targeting
  • Genes, Regulator / genetics*
  • Germ Cells / cytology
  • Germ Cells / growth & development
  • Germ Cells / metabolism
  • Male
  • Mice
  • Mice, Knockout
  • Microscopy, Electron
  • Myelin Sheath / genetics
  • Myelin Sheath / metabolism*
  • Myelin Sheath / pathology
  • Myelin Sheath / ultrastructure
  • Peripheral Nerves / growth & development*
  • Peripheral Nerves / metabolism
  • Peripheral Nerves / pathology
  • Phenotype
  • Protein Subunits / deficiency*
  • Protein Subunits / genetics
  • RNA Polymerase II / genetics
  • RNA Polymerase II / metabolism
  • Schwann Cells / metabolism*
  • Schwann Cells / pathology
  • Schwann Cells / ultrastructure
  • Sciatic Nerve / growth & development
  • Sciatic Nerve / metabolism
  • Sciatic Nerve / pathology
  • Transcription Factor TFIIH
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Transcription Factors, TFII / genetics
  • Transcription Factors, TFII / metabolism*
  • Wallerian Degeneration / genetics
  • Wallerian Degeneration / metabolism
  • Wallerian Degeneration / pathology

Substances

  • DNA-Binding Proteins
  • Early Growth Response Protein 2
  • Egr2 protein, mouse
  • Protein Subunits
  • Transcription Factors
  • Transcription Factors, TFII
  • Transcription Factor TFIIH
  • Cyclin-Dependent Kinases
  • RNA Polymerase II
  • Cyclin-Dependent Kinase-Activating Kinase