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

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