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

Cell Rep. 2018 Mar 27;22(13):3587-3597. doi: 10.1016/j.celrep.2018.02.102.


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.

Keywords: CNS injury; LZK; MAP3K; SOX9; STAT3; astroglial reactivity; astrogliosis; glial scar; reactive astrocytes; spinal cord injury.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Astrocytes / enzymology*
  • Astrocytes / pathology*
  • Central Nervous System / enzymology
  • Central Nervous System / pathology
  • Female
  • MAP Kinase Kinase Kinases / metabolism*
  • MAP Kinase Signaling System
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • SOX9 Transcription Factor / metabolism
  • STAT3 Transcription Factor / metabolism
  • Spinal Cord Injuries / enzymology*
  • Spinal Cord Injuries / pathology*
  • Up-Regulation


  • SOX9 Transcription Factor
  • STAT3 Transcription Factor
  • Sox9 protein, mouse
  • Stat3 protein, mouse
  • Lzk protein, mouse
  • MAP Kinase Kinase Kinases