Neuropilins: Their transcriptional regulation and role in ischemia-induced neuronal cell death

Abstract

Elucidation of molecular mechanisms modulating the death and failure of neurons to regenerate after cerebral ischemia is important in developing therapeutics to stroke. Here, results demonstrate that the pro-death transcription factor E2F1 inhibits neuronal survival through up-regulation of the receptor for axon repulsive guidance molecule, NRP-1. First, NRP-1 is shown as a direct target of E2F1 based on: reactivation of NRP-1 expression in E2F1-/- neurons after E2F1 replacement, EMSA and reporter assays confirming E2F1 binding and activation of the NRP-1 promoter, respectively. Second, pharmacological and genetic inhibition of NRP-1 conferred neuroprotection. Collectively, these findings support a model in which E2F1 targets NRP1 to modulate axonal damage and neuronal death in response to cerebral ischemia. Future work should determine the differential contributions of NRP-1 and NRP-2 in neuronal survival. Studies in vivo will also confirm the therapeutic benefit of inhibition of NRPs in stroke recovery.