Leucine Zipper-Bearing Kinase Is a Critical Regulator of Astrocyte Reactivity in the Adult Mammalian CNS

Meifan Chen, Cédric G. Geoffroy, Jessica M. Meves, Aarti Narang, Yunbo Li, Mallorie T. Nguyen, Vung S. Khai, Xiangmei Kong, Christopher L. Steinke, Krislyn I. Carolino, Lucie Elzière, Mark P. Goldberg, Yishi Jin, Binhai Zheng

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

Abstract

Reactive astrocytes influence post-injury recovery, repair, and pathogenesis of the mammalian CNS. Much of the regulation of astrocyte reactivity, however, remains to be understood. Using genetic loss and gain-of-function analyses in vivo, we show that the conserved MAP3K13 (also known as leucine zipper-bearing kinase [LZK]) promotes astrocyte reactivity and glial scar formation after CNS injury. Inducible LZK gene deletion in astrocytes of adult mice reduced astrogliosis and impaired glial scar formation, resulting in increased lesion size after spinal cord injury. Conversely, LZK overexpression in astrocytes enhanced astrogliosis and reduced lesion size. Remarkably, in the absence of injury, LZK overexpression alone induced widespread astrogliosis in the CNS and upregulated astrogliosis activators pSTAT3 and SOX9. The identification of LZK as a critical cell-intrinsic regulator of astrocyte reactivity expands our understanding of the multicellular response to CNS injury and disease, with broad translational implications for neural repair. Reactive astrocytes are recognized increasingly for their role in CNS injury and disease. Chen et al. find that leucine zipper-bearing kinase (LZK) is a positive regulator of astrocyte reactivity that controls glial scar formation after spinal cord injury. These findings have broad implications for understanding injury responses and promoting neural repair.

Original languageEnglish
Pages (from-to)3587-3597
Number of pages11
JournalCell Reports
Volume22
Issue number13
DOIs
StatePublished - Mar 27 2018

Bibliographical note

Funding Information:
This work was supported by an NIH National Research Service Award Individual Postdoctoral Fellowship (F32NS083186) to M.C., a grant from the Haggerty Foundation to M.P.G., funds from the Howard Hughes Medical Institute and the Craig H. Neilsen Foundation (award 316915) to Y.J., and grants from the NIH/National Institute of Neurological Disorders and Stroke (NS093055, NS054734, and NS047101), the Craig H. Neilsen Foundation (award 384971) and Wings for Life Spinal Cord Research Foundation (award WFL-US-27/17) to B.Z. We thank the Whole Brain Microscopy Facility (WBMF) at the University of Texas Southwestern for assistance with microscope use. The WBMF is supported by the Texas Institute for Brain Injury and Repair.

Funding Information:
This work was supported by an NIH National Research Service Award Individual Postdoctoral Fellowship ( F32NS083186 ) to M.C., a grant from the Haggerty Foundation to M.P.G., funds from the Howard Hughes Medical Institute and the Craig H. Neilsen Foundation (award 316915 ) to Y.J., and grants from the NIH/National Institute of Neurological Disorders and Stroke ( NS093055 , NS054734 , and NS047101 ), the Craig H. Neilsen Foundation (award 384971 ) and Wings for Life Spinal Cord Research Foundation (award WFL-US-27/17 ) to B.Z.. We thank the Whole Brain Microscopy Facility (WBMF) at the University of Texas Southwestern for assistance with microscope use. The WBMF is supported by the Texas Institute for Brain Injury and Repair .

Publisher Copyright:
© 2018 The Author(s)

Keywords

  • CNS injury
  • LZK
  • MAP3K
  • SOX9
  • STAT3
  • astroglial reactivity
  • astrogliosis
  • glial scar
  • reactive astrocytes
  • spinal cord injury

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology (all)

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