Activity-dependent regulation of axonal growth: posttranscriptional control of the GAP-43 gene by the NMDA receptor in developing hippocampus.
The intricate circuitry of the nervous system has been shown to be refined by activity-dependent processes often involving the glutamate N-methyl-D-aspartate (NMDA) receptor. NMDA receptor activity has been directly associated with axonal growth during development and in adult models of synaptic plasticity. The axonal growth-associated protein GAP-43 has been involved in the same processes as the NMDA receptor, but a direct link between the two has never been demonstrated in vivo. It is attractive to think that the NMDA receptor may regulate axonal growth through GAP-43. We tested this idea in outgrowing axons of hippocampal granule cells, the mossy fibers. Granule cells normally only express GAP-43 in an organized outside-in manner during a restricted period in postnatal development paralleling the pattern of axonal extension. Here, we show that during postnatal development in a transgenic mouse bearing a GAP-43 promoter/lacZ reporter construct, granule cells also display an outside-in pattern of promoter activation as indexed by transgene expression (PATE). In fact, PATE precedes axonal outgrowth with temporospatial fidelity. Since PATE deactivates on growth termination, the promoter may function as a switch for an intrinsic program of regulated axonal growth. The NMDA receptor antagonist MK-801 administered within a restricted time frame (4-8 days) results in a decrease in the extent and intensity of mossy fiber staining. While levels of GAP-43 mRNA are significantly reduced in granule cells, GAP-43 PATE is not. The level of GAP-43 expression and axonal growth during development appears to be dually controlled by a transcriptional program that is activity-independent and by a posttranscriptional mechanism that is activity-dependent and NMDA mediated.
Cantallops
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Cresap Neuroscience Laboratory, Northwestern University Institute for Neuroscience, Northwestern University, 2021 Sheridan Road, Evanston, Illinois 60208, USA.
Routtenberg
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D000818:Animals; D018891:Dentate Gyrus / Q000166:cytology / Q000196:embryology* / Q000254:growth & development; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005260:Female; D019922:GAP-43 Protein / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D007763:Lac Operon; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D019599:Mossy Fibers, Hippocampal / Q000737:chemistry / Q000187:drug effects / Q000502:physiology*; D011401:Promoter Regions, Genetic / Q000502:physiology; D012323:RNA Processing, Post-Transcriptional; D012333:RNA, Messenger / Q000032:analysis; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000502:physiology*; D019076:Transgenes / Q000502:physiology
D018691:Excitatory Amino Acid Antagonists; D019922:GAP-43 Protein; D012333:RNA, Messenger; D016194:Receptors, N-Methyl-D-Aspartate; D016291:Dizocilpine Maleate