DDIT4/REDD1/RTP801 is a novel negative regulator of Schwann cell myelination.
Signals that promote myelination must be tightly modulated to adjust myelin thickness to the axonal diameter. In the peripheral nervous system, axonal neuregulin 1 type III promotes myelination by activating erbB2/B3 receptors and the PI3K/AKT/mTOR pathway in Schwann cells. Conversely, PTEN (phosphatase and tensin homolog on chromosome 10) dephosphorylates PtdIns(3,4,5)P3 and negatively regulates the AKT pathway and myelination. Recently, the DLG1/SAP97 scaffolding protein was described to interact with PTEN to enhance PIP3 dephosphorylation. Here we now report that nerves from mice with conditional inactivation of Dlg1 in Schwann cells display only a transient increase in myelin thickness during development, suggesting that DLG1 is a transient negative regulator of myelination. Instead, we identified DDIT4/RTP801/REDD1 as a sustained negative modulator of myelination. We show that DDIT4 is expressed in Schwann cells and its maximum expression level precedes the peak of AKT activation and of DLG1 activity in peripheral nerves. Moreover, loss of DDIT4 expression both in vitro and in vivo in Ddit4-null mice provokes sustained hypermyelination and enhanced mTORC1 activation, thus suggesting that this molecule is a novel negative regulator of PNS myelination.
Dulbecco Telethon Institute at Institute of Experimental Neurology (INSPE), San Raffaele Scientific Institute, 20132 Milan, Italy, UniSR, Vita Salute San Raffaele University, 20132 Milan, Italy, Institute of Experimental Neurology (INSPE), San Raffaele Scientific Institute, 20132 Milan, Italy, Hunter James Kelly Research Institute, University at Buffalo, State University of New York, Buffalo, New York 14203, Quark Pharmaceuticals, 70400 Ness Ziona, Israel, and The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
Roberta
R
Noseda
Sophie
S
Belin
Françoise
F
Piguet
Ilaria
I
Vaccari
Stefania
S
Scarlino
Paola
P
Brambilla
Filippo
F
Martinelli Boneschi
Maria Laura
ML
Feltri
Lawrence
L
Wrabetz
Angelo
A
Quattrini
Elena
E
Feinstein
Richard L
RL
Huganir
Alessandra
A
Bolino
D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D018920:Coculture Techniques; D000074288:Discs Large Homolog 1 Protein; D004622:Embryo, Mammalian; D005727:Ganglia, Spinal / Q000166:cytology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D004676:Myelin Basic Protein / Q000378:metabolism; D018993:Myelin P0 Protein / Q000378:metabolism; D009186:Myelin Sheath / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000235:genetics; D016900:Neurofilament Proteins / Q000378:metabolism; D009474:Neurons / Q000502:physiology; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D000074407:SAP90-PSD95 Associated Proteins; D012583:Schwann Cells / Q000502:physiology* / Q000648:ultrastructure; D012584:Sciatic Nerve / Q000378:metabolism / Q000648:ultrastructure; D014157:Transcription Factors / Q000172:deficiency / Q000502:physiology*; D014161:Transduction, Genetic
C469992:Ddit4 protein, mouse; D000074288:Discs Large Homolog 1 Protein; C000614189:Dlg1 protein, mouse; C499047:Mbp protein, mouse; D004676:Myelin Basic Protein; D018993:Myelin P0 Protein; D009419:Nerve Tissue Proteins; D016900:Neurofilament Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D000074407:SAP90-PSD95 Associated Proteins; D014157:Transcription Factors; C044882:neurofilament protein L