DDIT4/REDD1/RTP801 is a novel negative regulator of schwann cell myelination

Roberta Noseda, Sophie Belin, Francoise Piguet, Ilaria Vaccari, Stefania Scarlino, Paola Brambilla, Filippo Martinelli Boneschi, Maria Laura Feltri, Lawrence Wrabetz, Angelo Quattrini, Elena Feinstein, Richard L Huganir, Alessandra Bolino

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)15295-15305
Number of pages11
JournalJournal of Neuroscience
Volume33
Issue number38
DOIs
StatePublished - 2013

Fingerprint

Schwann Cells
Myelin Sheath
PTEN Phosphohydrolase
Neuregulin-1
Chromosomes, Human, Pair 10
Peripheral Nervous System
Phosphatidylinositol 3-Kinases
Peripheral Nerves
Proteins

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Noseda, R., Belin, S., Piguet, F., Vaccari, I., Scarlino, S., Brambilla, P., ... Bolino, A. (2013). DDIT4/REDD1/RTP801 is a novel negative regulator of schwann cell myelination. Journal of Neuroscience, 33(38), 15295-15305. https://doi.org/10.1523/JNEUROSCI.2408-13.2013

DDIT4/REDD1/RTP801 is a novel negative regulator of schwann cell myelination. / Noseda, Roberta; Belin, Sophie; Piguet, Francoise; Vaccari, Ilaria; Scarlino, Stefania; Brambilla, Paola; Boneschi, Filippo Martinelli; Feltri, Maria Laura; Wrabetz, Lawrence; Quattrini, Angelo; Feinstein, Elena; Huganir, Richard L; Bolino, Alessandra.

In: Journal of Neuroscience, Vol. 33, No. 38, 2013, p. 15295-15305.

Research output: Contribution to journalArticle

Noseda, R, Belin, S, Piguet, F, Vaccari, I, Scarlino, S, Brambilla, P, Boneschi, FM, Feltri, ML, Wrabetz, L, Quattrini, A, Feinstein, E, Huganir, RL & Bolino, A 2013, 'DDIT4/REDD1/RTP801 is a novel negative regulator of schwann cell myelination', Journal of Neuroscience, vol. 33, no. 38, pp. 15295-15305. https://doi.org/10.1523/JNEUROSCI.2408-13.2013
Noseda R, Belin S, Piguet F, Vaccari I, Scarlino S, Brambilla P et al. DDIT4/REDD1/RTP801 is a novel negative regulator of schwann cell myelination. Journal of Neuroscience. 2013;33(38):15295-15305. https://doi.org/10.1523/JNEUROSCI.2408-13.2013
Noseda, Roberta ; Belin, Sophie ; Piguet, Francoise ; Vaccari, Ilaria ; Scarlino, Stefania ; Brambilla, Paola ; Boneschi, Filippo Martinelli ; Feltri, Maria Laura ; Wrabetz, Lawrence ; Quattrini, Angelo ; Feinstein, Elena ; Huganir, Richard L ; Bolino, Alessandra. / DDIT4/REDD1/RTP801 is a novel negative regulator of schwann cell myelination. In: Journal of Neuroscience. 2013 ; Vol. 33, No. 38. pp. 15295-15305.
@article{d8a04526b5724a9da81a1610f3758cc9,
title = "DDIT4/REDD1/RTP801 is a novel negative regulator of schwann cell myelination",
abstract = "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.",
author = "Roberta Noseda and Sophie Belin and Francoise Piguet and Ilaria Vaccari and Stefania Scarlino and Paola Brambilla and Boneschi, {Filippo Martinelli} and Feltri, {Maria Laura} and Lawrence Wrabetz and Angelo Quattrini and Elena Feinstein and Huganir, {Richard L} and Alessandra Bolino",
year = "2013",
doi = "10.1523/JNEUROSCI.2408-13.2013",
language = "English (US)",
volume = "33",
pages = "15295--15305",
journal = "Journal of Neuroscience",
issn = "0270-6474",
publisher = "Society for Neuroscience",
number = "38",

}

TY - JOUR

T1 - DDIT4/REDD1/RTP801 is a novel negative regulator of schwann cell myelination

AU - Noseda, Roberta

AU - Belin, Sophie

AU - Piguet, Francoise

AU - Vaccari, Ilaria

AU - Scarlino, Stefania

AU - Brambilla, Paola

AU - Boneschi, Filippo Martinelli

AU - Feltri, Maria Laura

AU - Wrabetz, Lawrence

AU - Quattrini, Angelo

AU - Feinstein, Elena

AU - Huganir, Richard L

AU - Bolino, Alessandra

PY - 2013

Y1 - 2013

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84884175477&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84884175477&partnerID=8YFLogxK

U2 - 10.1523/JNEUROSCI.2408-13.2013

DO - 10.1523/JNEUROSCI.2408-13.2013

M3 - Article

C2 - 24048858

AN - SCOPUS:84884175477

VL - 33

SP - 15295

EP - 15305

JO - Journal of Neuroscience

JF - Journal of Neuroscience

SN - 0270-6474

IS - 38

ER -