A paradigm for distinguishing the roles of mitogenesis and trophism in neuronal precursor proliferation.
During nervous system development, the generation of neuronal populations is subject to regulation by extracellular growth factors. Traditional views suggest that growth factors promote proliferation by increasing the fraction of precursors that enter the mitotic cycle and subsequently divide (that is, enhance mitosis). However, recent evidence indicates that dividing precursors may undergo cell death. Consequently, a given molecule may also increase neuroblast proliferation by promoting survival of dividing precursors. In the present work, we developed a new approach to distinguish these two distinct effects of growth factors on dividing neuroblasts. By using a brief 6 h culture paradigm of embryonic day 15.5 sympathetic neuroblasts, we minimized cell death, thereby excluding the survival-promoting (trophic) activity of growth factors. In the absence of trophism, measured increases in [3H]thymidine incorporation reflected growth factor mitogenic activity only. Using a well-characterized sympathetic model, we found that insulin, EGF and vasoactive intestinal peptide (VIP) increased [3H]thymidine incorporation 30%, 20% and 46% respectively, consistent with their previously reported mitogenic activity. In contrast, neurotrophin-3 (NT3) and nerve growth factor (NGF), which serve as trophic signals for the neuroblasts, did not elicit any change in [3H]thymidine incorporation, indicating that the neurotrophins are not mitogenic for sympathetic precursors. This approach may be useful in distinguishing mitogenic and trophic regulation of proliferation in other brain precursor populations.
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Department of Neuroscience and Cell Biology, UMDNJ/Robert Wood Johnson Medical School, Piscataway 08854, USA.
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DiCicco-Bloom
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D000818:Animals; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured / Q000166:cytology / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000494:pharmacology; D007328:Insulin / Q000494:pharmacology; D008934:Mitogens / Q000494:pharmacology*; D008938:Mitosis / Q000502:physiology; D009414:Nerve Growth Factors / Q000494:pharmacology; D009474:Neurons / Q000166:cytology* / Q000187:drug effects; D020933:Neurotrophin 3; D051381:Rats; D013234:Stem Cells / Q000166:cytology* / Q000187:drug effects; D013564:Sympathetic Nervous System / Q000166:cytology; D018523:Tropism / Q000502:physiology*; D014660:Vasoactive Intestinal Peptide / Q000494:pharmacology
D007328:Insulin; D008934:Mitogens; D009414:Nerve Growth Factors; D020933:Neurotrophin 3; D014660:Vasoactive Intestinal Peptide; D004815:Epidermal Growth Factor