Ependymal Yes‐Associated Protein Promotes the Neural Regeneration Through Enhancing the Ependymal Cell‐Derived Perilesional Glial Borders in Mice After Spinal Cord Injury

ABSTRACT Objectives Ependymal cell‐derived perilesional glial borders may play a beneficial role in neural regeneration after spinal cord injury (SCI). Yes‐associated protein (YAP), a key transcriptional cofactor, is involved in the control of body organ size by regulating cell differentiation, proliferation, growth, and apoptosis; however, it remains unclear whether the roles and underlying mechanisms of YAP signaling regulate the ependymal cell‐derived perilesional glial borders after SCI. Methods We established a dorsal cord incision injury mouse model. The YAP f/f ; FoxJ1‐CreERT2 (YAP FoxJ1‐ERT2 ‐CKO) mice and YAP f/f ; FoxJ1‐CreERT2; Rosa26 tdTomato mice were generated to examine the roles of ependymal YAP signaling in SCI. The RNA‐seq, western blot, immunostaining, and cell‐fate tracing tools were used to investigate the underlying mechanisms of YAP signaling in the regulation of ependymal cell‐derived perilesional glial borders after SCI. Results YAP was activated in ependymal cells after SCI. Interestingly, YAP deletion in ependymal cells (YAP FoxJ1‐ERT2 ‐CKO mice) aggravated the neuronal loss and impaired the formation of perilesional glial borders and then inhibited the functional recovery after SCI. Furthermore, YAP deletion inhibited the proliferation and differentiation of ependymal cells to astrocytes and oligodendrocytes and reduced the secretion of neurotrophic factors after SCI. Mechanically, RNA‐seq revealed that the expression of Colorectal Neoplasia Differentially Expressed (CRNDE) was downregulated in YAP FoxJ1‐ERT2 ‐CKO mice. Furthermore, we found downregulation of P300 and β‐catenin and upregulation of GSK‐3β in YAP −/− ependymal cells after SCI. Conclusion Ependymal YAP signaling promotes the formation of ependymal cell‐derived perilesional glial borders in mice through the P300‐CRNDE‐Wnt/β‐catenin pathway after SCI, which provides a novel target for SCI.