Conditional ablation of the Mat1 subunit of TFIIH in Schwann cells provides evidence that Mat1 is not required for general transcription.
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.
Korsisaari
Nina
N
Haartman Institute and Helsinki University Central Hospital, Biomedicum Helsinki, PO Box 63, Haartmaninkatu 8, 00014 University of Helsinki, Finland.
Rossi
Derrick J
DJ
Paetau
Anders
A
Charnay
Patrick
P
Henkemeyer
Mark
M
Mäkelä
Tomi P
TP
D000818:Animals; D002455:Cell Division / Q000235:genetics; D019070:Cell Lineage / Q000235:genetics; D018844:Cyclin-Dependent Kinases / Q000172:deficiency* / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D051767:Early Growth Response Protein 2; D005260:Female; D018390:Gene Targeting; D005809:Genes, Regulator / Q000235:genetics*; D005854:Germ Cells / Q000166:cytology / Q000254:growth & development / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008854:Microscopy, Electron; D009186:Myelin Sheath / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D010525:Peripheral Nerves / Q000254:growth & development* / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D021122:Protein Subunits / Q000172:deficiency* / Q000235:genetics; D012319:RNA Polymerase II / Q000235:genetics / Q000378:metabolism; D012583:Schwann Cells / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D012584:Sciatic Nerve / Q000254:growth & development / Q000378:metabolism / Q000473:pathology; D051758:Transcription Factor TFIIH; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D019473:Transcription Factors, TFII / Q000235:genetics / Q000378:metabolism*; D014855:Wallerian Degeneration / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000095043:Cyclin-Dependent Kinase-Activating Kinase
D004268:DNA-Binding Proteins; D051767:Early Growth Response Protein 2; C497327:Egr2 protein, mouse; D021122:Protein Subunits; D014157:Transcription Factors; D019473:Transcription Factors, TFII; D051758:Transcription Factor TFIIH; D018844:Cyclin-Dependent Kinases; D012319:RNA Polymerase II; D000095043:Cyclin-Dependent Kinase-Activating Kinase