A purine-sensitive mechanism regulates the molecular program for axon growth.
Axon growth is characterized by a distinctive program of gene expression. We present evidence here that this program is regulated through a purine-sensitive mechanism, and that it can be re-activated in mature CNS neurons to induce extensive axon growth in vitro and in vivo. In dissociated goldfish retinal ganglion cells, the purine nucleoside inosine acts intracellularly to stimulate axon outgrowth by inducing the expression of GAP-43, Talpha-1 tubulin, and other growth-associated proteins. The purine analog 6-thioguanine (6-TG) acts in the opposite fashion, blocking axon growth and the underlying program of molecular changes. Prior studies in PC12 cells have shown that 6-TG selectively inhibits the activity of N-kinase, a 47-49 kDa serine-threonine kinase. Inosine acts as a competitor of 6-TG, suggesting that it acts as an N-kinase agonist, and that this kinase is part of a modular signal transduction pathway controlling axon growth. Following unilateral transections of the corticospinal tract in mature rats, inosine applied to the intact sensorimotor cortex stimulated layer 5 pyramidal cells to upregulate GAP-43 expression and to sprout axon collaterals that crossed the midline and reinnervated regions of the cervical spinal cord which had lost their normal afferents. It will now be important to identify the molecular changes that lie upstream and downstream of N-kinase, and to explore the clinical potential of activating this pathway in patients who have sustained CNS injury.
Benowitz
L I
LI
Laboratories for Neuroscience Research in Neurosurgery, Children's Hospital, Boston MA 02115, USA. larry.benowitz@tch.harvard.edu
Goldberg
D E
DE
Irwin
N
N
D000818:Animals; D001369:Axons / Q000502:physiology*; D002455:Cell Division / Q000502:physiology; D006801:Humans; D007288:Inosine / Q000737:chemistry / Q000502:physiology; D011687:Purines / Q000737:chemistry / Q000494:pharmacology*; D012165:Retinal Ganglion Cells / Q000166:cytology / Q000502:physiology; D013116:Spinal Cord / Q000166:cytology / Q000502:physiology
D011687:Purines; D007288:Inosine; C030985:purine