The Transcriptional Activator Krüppel-like Factor-6 Is Required for CNS Myelination

Benjamin M. Laitman; Linnéa Asp; John N. Mariani; Jingya Zhang; Jia Liu; Setsu Sawai; Candice Chapouly; Sam Horng; Elisabeth G. Kramer; Nesanet Mitiku; Hannah Loo; Natalie Burlant; Xiomara Pedre; Yuko Hara; German Nudelman; Elena Zaslavsky; Young Min Lee; David A. Braun; Q. Richard Lu; Goutham Narla; Cedric S. Raine; Scott L. Friedman; Patrizia Casaccia; Gareth R. John

doi:10.1371/journal.pbio.1002467

The Transcriptional Activator Krüppel-like Factor-6 Is Required for CNS Myelination

Benjamin M. Laitman, Linnéa Asp, John N. Mariani, Jingya Zhang, Jia Liu, Setsu Sawai, Candice Chapouly, Sam Horng, Elisabeth G. Kramer, Nesanet Mitiku, Hannah Loo, Natalie Burlant, Xiomara Pedre, Yuko Hara, German Nudelman, Elena Zaslavsky, Young Min Lee, David A. Braun, Q. Richard Lu, Goutham NarlaCedric S. Raine, Scott L. Friedman, Patrizia Casaccia, Gareth R. John

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Abstract

Growth factors of the gp130 family promote oligodendrocyte differentiation, and viability, and myelination, but their mechanisms of action are incompletely understood. Here, we show that these effects are coordinated, in part, by the transcriptional activator Krüppel-like factor-6 (Klf6). Klf6 is rapidly induced in oligodendrocyte progenitors (OLP) by gp130 factors, and promotes differentiation. Conversely, in mice with lineage-selective Klf6 inactivation, OLP undergo maturation arrest followed by apoptosis, and CNS myelination fails. Overlapping transcriptional and chromatin occupancy analyses place Klf6 at the nexus of a novel gp130-Klf-importin axis, which promotes differentiation and viability in part via control of nuclear trafficking. Klf6 acts as a gp130-sensitive transactivator of the nuclear import factor importin-α5 (Impα5), and interfering with this mechanism interrupts step-wise differentiation. Underscoring the significance of this axis in vivo, mice with conditional inactivation of gp130 signaling display defective Klf6 and Impα5 expression, OLP maturation arrest and apoptosis, and failure of CNS myelination.

Original language	English
Article number	e1002467
Journal	PLoS Biology
Volume	14
Issue number	5
DOIs	https://doi.org/10.1371/journal.pbio.1002467
State	Published - 23 May 2016

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Laitman, B. M., Asp, L., Mariani, J. N., Zhang, J., Liu, J., Sawai, S., Chapouly, C., Horng, S., Kramer, E. G., Mitiku, N., Loo, H., Burlant, N., Pedre, X., Hara, Y., Nudelman, G., Zaslavsky, E., Lee, Y. M., Braun, D. A., Lu, Q. R., ... John, G. R. (2016). The Transcriptional Activator Krüppel-like Factor-6 Is Required for CNS Myelination. PLoS Biology, 14(5), Article e1002467. https://doi.org/10.1371/journal.pbio.1002467

@article{398fa61d69b44049b95a102d6a28f742,

title = "The Transcriptional Activator Kr{\"u}ppel-like Factor-6 Is Required for CNS Myelination",

abstract = "Growth factors of the gp130 family promote oligodendrocyte differentiation, and viability, and myelination, but their mechanisms of action are incompletely understood. Here, we show that these effects are coordinated, in part, by the transcriptional activator Kr{\"u}ppel-like factor-6 (Klf6). Klf6 is rapidly induced in oligodendrocyte progenitors (OLP) by gp130 factors, and promotes differentiation. Conversely, in mice with lineage-selective Klf6 inactivation, OLP undergo maturation arrest followed by apoptosis, and CNS myelination fails. Overlapping transcriptional and chromatin occupancy analyses place Klf6 at the nexus of a novel gp130-Klf-importin axis, which promotes differentiation and viability in part via control of nuclear trafficking. Klf6 acts as a gp130-sensitive transactivator of the nuclear import factor importin-α5 (Impα5), and interfering with this mechanism interrupts step-wise differentiation. Underscoring the significance of this axis in vivo, mice with conditional inactivation of gp130 signaling display defective Klf6 and Impα5 expression, OLP maturation arrest and apoptosis, and failure of CNS myelination.",

author = "Laitman, {Benjamin M.} and Linn{\'e}a Asp and Mariani, {John N.} and Jingya Zhang and Jia Liu and Setsu Sawai and Candice Chapouly and Sam Horng and Kramer, {Elisabeth G.} and Nesanet Mitiku and Hannah Loo and Natalie Burlant and Xiomara Pedre and Yuko Hara and German Nudelman and Elena Zaslavsky and Lee, {Young Min} and Braun, {David A.} and Lu, {Q. Richard} and Goutham Narla and Raine, {Cedric S.} and Friedman, {Scott L.} and Patrizia Casaccia and John, {Gareth R.}",

note = "Publisher Copyright: {\textcopyright} 2016 Laitman et al.",

year = "2016",

month = may,

day = "23",

doi = "10.1371/journal.pbio.1002467",

language = "English",

volume = "14",

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Laitman, BM, Asp, L, Mariani, JN, Zhang, J, Liu, J, Sawai, S, Chapouly, C, Horng, S, Kramer, EG, Mitiku, N, Loo, H, Burlant, N, Pedre, X, Hara, Y, Nudelman, G, Zaslavsky, E, Lee, YM, Braun, DA, Lu, QR, Narla, G, Raine, CS, Friedman, SL, Casaccia, P & John, GR 2016, 'The Transcriptional Activator Krüppel-like Factor-6 Is Required for CNS Myelination', PLoS Biology, vol. 14, no. 5, e1002467. https://doi.org/10.1371/journal.pbio.1002467

TY - JOUR

T1 - The Transcriptional Activator Krüppel-like Factor-6 Is Required for CNS Myelination

AU - Laitman, Benjamin M.

AU - Asp, Linnéa

AU - Mariani, John N.

AU - Zhang, Jingya

AU - Liu, Jia

AU - Sawai, Setsu

AU - Chapouly, Candice

AU - Horng, Sam

AU - Kramer, Elisabeth G.

AU - Mitiku, Nesanet

AU - Loo, Hannah

AU - Burlant, Natalie

AU - Pedre, Xiomara

AU - Hara, Yuko

AU - Nudelman, German

AU - Zaslavsky, Elena

AU - Lee, Young Min

AU - Braun, David A.

AU - Lu, Q. Richard

AU - Narla, Goutham

AU - Raine, Cedric S.

AU - Friedman, Scott L.

AU - Casaccia, Patrizia

AU - John, Gareth R.

PY - 2016/5/23

Y1 - 2016/5/23

N2 - Growth factors of the gp130 family promote oligodendrocyte differentiation, and viability, and myelination, but their mechanisms of action are incompletely understood. Here, we show that these effects are coordinated, in part, by the transcriptional activator Krüppel-like factor-6 (Klf6). Klf6 is rapidly induced in oligodendrocyte progenitors (OLP) by gp130 factors, and promotes differentiation. Conversely, in mice with lineage-selective Klf6 inactivation, OLP undergo maturation arrest followed by apoptosis, and CNS myelination fails. Overlapping transcriptional and chromatin occupancy analyses place Klf6 at the nexus of a novel gp130-Klf-importin axis, which promotes differentiation and viability in part via control of nuclear trafficking. Klf6 acts as a gp130-sensitive transactivator of the nuclear import factor importin-α5 (Impα5), and interfering with this mechanism interrupts step-wise differentiation. Underscoring the significance of this axis in vivo, mice with conditional inactivation of gp130 signaling display defective Klf6 and Impα5 expression, OLP maturation arrest and apoptosis, and failure of CNS myelination.

AB - Growth factors of the gp130 family promote oligodendrocyte differentiation, and viability, and myelination, but their mechanisms of action are incompletely understood. Here, we show that these effects are coordinated, in part, by the transcriptional activator Krüppel-like factor-6 (Klf6). Klf6 is rapidly induced in oligodendrocyte progenitors (OLP) by gp130 factors, and promotes differentiation. Conversely, in mice with lineage-selective Klf6 inactivation, OLP undergo maturation arrest followed by apoptosis, and CNS myelination fails. Overlapping transcriptional and chromatin occupancy analyses place Klf6 at the nexus of a novel gp130-Klf-importin axis, which promotes differentiation and viability in part via control of nuclear trafficking. Klf6 acts as a gp130-sensitive transactivator of the nuclear import factor importin-α5 (Impα5), and interfering with this mechanism interrupts step-wise differentiation. Underscoring the significance of this axis in vivo, mice with conditional inactivation of gp130 signaling display defective Klf6 and Impα5 expression, OLP maturation arrest and apoptosis, and failure of CNS myelination.

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U2 - 10.1371/journal.pbio.1002467

DO - 10.1371/journal.pbio.1002467

M3 - Article

C2 - 27213272

AN - SCOPUS:84971631274

SN - 1544-9173

VL - 14

JO - PLoS Biology

JF - PLoS Biology

IS - 5

M1 - e1002467

ER -

The Transcriptional Activator Krüppel-like Factor-6 Is Required for CNS Myelination

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