Transcription factor activator protein 4 (AP4)–mediated intrinsic control of axon regeneration

Abstract

Activator protein 4 (AP4) is a basic helix-loop-helix leucine-zipper transcription factor, a direct transcriptional target of c-Myc and a key regulator of cell growth and apoptosis, abundantly expressed in cancer cells. Here, we reveal a role for the c-Myc–AP4 axis in axon regeneration and the intrinsic growth capacity of injured neurons. Through bioinformatic and functional analyses, we demonstrated that overexpression of AP4 in mice not only accelerated in vivo axon regeneration and functional recovery after peripheral nerve injury but also promoted robust axon regeneration and neuronal survival after optic nerve injury by activating mammalian target of rapamycin activity. Neuronal-specific knockdown of AP4 abolished the regenerative phenotype induced by c-Myc overexpression and phosphatase and tensin homolog (PTEN) deletion. AP4 overexpression rendered the intrinsic growth capacity of c-Myc silencing injured retinal ganglion cells unaffected. These findings unveil a distinct aspect of the c-Myc–AP4 axis and highlight a previously unrecognized intrinsic role of AP4 in axon regeneration, with potential therapeutic implications.