Morphological regulation of wound repair astrocytes by leucine zipper-bearing kinase-AKT signaling after spinal cord injury

Abstract

Following focal CNS injury, a salient feature of astrocytes lining the lesion is their remarkable morphological transformation into an interwoven cellular border that serves their protective function in wound closure. Despite the importance of morphology in determining function of lesion border astrocytes and injury outcome, there is sparse knowledge of how cell shape is regulated temporally and mechanistically in border-forming astrocytes. We report a transcriptional program of actin and microtubule reorganization that is induced in lesion border astrocytes after spinal cord injury in mice. By genetic gain- and loss-of-function analyses in vivo, we show that leucine zipper-bearing kinase (LZK) is a positive regulator of injury-responsive transcription of cytoskeleton remodeling genes in lesion border astrocytes, with consequences on morphological adaptation of border-forming astrocytes. Functional validation of LZK-dependent cytoskeleton rearrangement in vitro demonstrates its ability to enhance astrocytic process extension, cell movement, and associated structural reorganization of actin and microtubules. We further identify LZK-dependent activation of AKT in astrocytes in vitro and in vivo, which is required for transcriptional regulation of the cytoskeleton by LZK, and to a similar extent as STAT3. Lastly, loss of astrocytic LZK impairs motor recovery after spinal cord injury. Our findings define temporal and molecular regulation of morphological transformation of lesion border astrocytes that may be targeted for CNS repair.