Neuronal replacement from neural stem cells (NSC) in brain lesions is ineffective and does not complete regeneration or functional recovery. After a brain lesion, neural stem cells are recruited to the peri-lesion area, but generate few neurons because of signals that promote glial differentiation or death of neural progenitors. Our laboratory studies mechanisms underlying neurogenesis deficiency within brain lesions and elucidated that ADAM17/TACE and PKCε play an important role in determining neuronal fate of neural progenitors. In addition we have designed strategies to modulate ADAM17/TACE and PKC activity in vitro and in vivo in mechanical brain lesions of the cerebral cortex achieving a substantial increase in neurogenesis.