The aPKC-CBP Pathway Regulates Post-stroke Neurovascular Remodeling and Functional Recovery

Epigenetic modifications have emerged as attractive molecular substrates that integrate extrinsic changes into the determination of cell identity. Since stroke-related brain damage releases micro-environmental cues, we examined the role of a signaling-induced epigenetic pathway, an atypical protein kinase C (aPKC)-mediated phosphorylation of CREB-binding protein (CBP), in post-stroke neurovascular remodeling. Using a knockin mouse strain (CbpS436A) where the aPKC-CBP pathway was defective, we show that disruption of the aPKC-CBP pathway in a murine focal ischemic stroke model increases the reprogramming efficiency of ischemia-activated pericytes (i-pericytes) to neural precursors. As a consequence of enhanced cellular reprogramming, CbpS436A mice show an increased transient population of locally derived neural precursors after stroke, while displaying a reduced number of i-pericytes, impaired vascular remodeling, and perturbed motor recovery during the chronic phase of stroke. Together, this study elucidates the role of the aPKC-CBP pathway in modulating neurovascular remodeling and functional recovery following focal ischemic stroke. Wang and colleagues used a knockin mouse model CbpS436A to show that the disruption of the aPKC-CBP pathway increases the reprogramming efficiency of ischemia-activated pericytes to neural precursors (NPCs). As an outcome, CbpS436A mice show an increase in the transient population of locally derived NPCs shortly after stroke, while displaying a reduced number of pericytes and impaired vascular remodeling and motor recovery during the chronic phase of stroke.