LITAF (SIMPLE) regulates Wallerian degeneration after injury but is not essential for peripheral nerve development and maintenance: implications for Charcot-Marie-Tooth disease.
Missense mutations affecting the LITAF gene (also known as SIMPLE) lead to the dominantly inherited peripheral neuropathy Charcot-Marie-Tooth disease type 1C (CMT1C). In this study, we sought to determine the requirement of Litaf function in peripheral nerves, the only known affected tissue in CMT1C. We reasoned that this knowledge is a prerequisite for a thorough understanding of the underlying disease mechanism with regard to potential contributions by Litaf loss of function. In addition, we anticipated to obtain valuable information about the basic function of the Litaf protein in peripheral nerves. To address these issues, we generated mice without Litaf expression using gene disruption in embryonic stem cells and analyzed Litaf-deficient peripheral nerves during development, in maintenance, and after injury. Our results show that Litaf function is not absolutely required for peripheral nerve development and maintenance. In injured nerves, however, we found that lack of Litaf led to increased numbers of macrophages during Wallerian degeneration, accelerated myelin destruction, and the emergence of more axonal sprouts. Consistent with these data, the migration of Litaf-deficient macrophages was increased upon chemokine stimulation. We conclude that loss of Litaf function is unlikely to be a major contributor to CMT1C, but modulating effects of macrophages need to be considered in the etiology of the disease.
Department of Biology, Institute of Molecular Health Sciences, Cell Biology, Swiss Federal Institute of Technology, ETH Zurich, CH-8093 Zurich, Switzerland.
Christian
C
Somandin
Daniel
D
Gerber
Jorge A
JA
Pereira
Michael
M
Horn
Ueli
U
Suter
D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D004268:DNA-Binding Proteins; D004195:Disease Models, Animal; D018507:Gene Expression Regulation, Developmental / Q000235:genetics / Q000502:physiology*; D008264:Macrophages / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission; D009154:Mutation / Q000235:genetics; D009186:Myelin Sheath / Q000378:metabolism; D009412:Nerve Fibers / Q000473:pathology / Q000648:ultrastructure; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010525:Peripheral Nerves / Q000254:growth & development* / Q000378:metabolism* / Q000648:ultrastructure; D020426:Sciatic Neuropathy / Q000150:complications / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014855:Wallerian Degeneration / Q000209:etiology / Q000378:metabolism* / Q000473:pathology
D004268:DNA-Binding Proteins; C492727:Litaf protein, mouse; D009687:Nuclear Proteins; D014157:Transcription Factors