Differential regulation of axon outgrowth and reinnervation by neurotrophin-3 and neurotrophin-4 in the hippocampal formation.
In this study, we investigated the hypothesis whether neurotrophins have a differential influence on neurite growth from the entorhinal cortex depending on the presence or absence of hippocampal target tissue. We investigated organotypic brain slices derived from the entorhinal-hippocampal system to analyze the effects of endogenous and recombinant neurotrophin-3 (NT-3) and neurotrophin-4 (NT-4) on neurite outgrowth and reinnervation. In the reinnervation assay, entorhinal cortex explants of transgenic mice expressing enhanced green fluorescent protein (EGFP) were co-cultured with wild-type hippocampi under the influence of recombinant NT-3 and NT-4 (500 ng/ml). Both recombinant NT-3 and NT-4 significantly increased the growth of EGFP+ nerve fibers into the target tissue. Consistently, reinnervation of the hippocampi of NT-4(-/-) and NT-3(+/-)NT-4(-/-) mice was substantially reduced. In contrast, the outgrowth assay did not exhibit reduction in axon outgrowth of NT-4(-/-) or NT-3(+/-)NT-4(-/-) cortex explants, while the application of recombinant NT-3 (500 ng/ml) induced a significant increase in the neurite extension of cortex explants. Recombinant NT-4 had no effect. In summary, only recombinant NT-3 stimulates axon outgrowth from cortex explants, while both endogenous and recombinant NT-3 and NT-4 synergistically promote reinnervation of the denervated hippocampus. These results suggest that endogenous and exogenous NT-3 and NT-4 differentially influence neurite growth depending on the presence or absence of target tissue.
Hechler
Daniel
D
Institute for Cell Biology and Neurobiology, Center for Anatomy, Charité, Universitätsmedizin, Berlin, Germany.
Boato
Francesco
F
Nitsch
Robert
R
Hendrix
Sven
S
D000818:Animals; D001369:Axons / Q000187:drug effects / Q000502:physiology*; D002227:Carbazoles / Q000494:pharmacology; D018728:Entorhinal Cortex / Q000166:cytology / Q000254:growth & development / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000254:growth & development / Q000502:physiology*; D026121:Indole Alkaloids / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009414:Nerve Growth Factors / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D009416:Nerve Regeneration / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D009474:Neurons / Q000502:physiology; D020933:Neurotrophin 3 / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D017475:Receptors, Nerve Growth Factor / Q000037:antagonists & inhibitors; D011994:Recombinant Proteins / Q000494:pharmacology
D002227:Carbazoles; D004791:Enzyme Inhibitors; D026121:Indole Alkaloids; D009414:Nerve Growth Factors; D020933:Neurotrophin 3; D017475:Receptors, Nerve Growth Factor; D011994:Recombinant Proteins; C049985:staurosporine aglycone; C073922:neurotrophin 4