Cortical interneurons upregulate neurotrophins in vivo in response to targeted apoptotic degeneration of neighboring pyramidal neurons.
Intercellular signals provided by growth and neurotrophic factors play a critical role during neurogenesis and as part of cellular repopulation strategies directed toward reconstruction of complex CNS circuitry. Local signals influence the differentiation of transplanted and endogenous neurons and neural precursors, but the cellular sources and control over expression of these molecules remain unclear. We have previously examined microenvironmental control in neocortex over neuron and neural precursor migration and differentiation following transplantation, using an approach of targeted apoptotic neuronal degeneration to specific neuronal populations in vivo. Prior results suggested the hypothesis that upregulated or reexpressed developmental signal molecules, produced by degenerating pyramidal neurons and/or by neighboring neurons or nonneuronal cells, may be responsible for observed events of directed migration, differentiation, and connectivity by transplanted immature neurons and precursors. To directly investigate this hypothesis, we analyzed the gene expression of candidate and control neurotrophins, growth factors, and receptors within regions of targeted neuronal cell death, first by quantitative Northern blot analysis and then by in situ hybridization combined with immunocytochemical analysis. The genes for BDNF, NT-4/5, trkB receptors, and to a lesser extent NT-3 were upregulated specifically within the regions of neocortex undergoing targeted neuronal degeneration and specifically during the period of ongoing pyramidal neuron apoptosis. Upregulation occurred during the same 3-week period as the previously investigated cellular events of directed migration, differentiation, and integration. No upregulation was seen in panels of control neurotrophins, growth factors, and receptors that are not as developmentally regulated in cortex or that are thought to have primary actions in other CNS regions. In situ hybridization and immunocytochemistry revealed that BDNF mRNA expression was upregulated specifically by local interneurons adjacent to degenerating pyramidal neurons. These findings suggest specific effects of targeted apoptosis on neurotrophin and other gene expression via mechanisms, including intercellular signaling between degenerating pyramidal neurons and surrounding interneurons. Further understanding of these and other controls over neocortical projection neuron differentiation may provide insight regarding normal neocortical development, intercellular signaling induced by apoptosis, and toward reconstruction and cellular repopulation of complex neocortical and other CNS circuitry.
Wang
Y
Y
Department of Neurology and Program in Neuroscience, Children's Hospital, Harvard Medical School, Boston, Massachusetts, 02115, USA.
Sheen
V L
VL
Macklis
J D
JD
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D015152:Blotting, Northern; D016380:Brain Tissue Transplantation; D019208:Brain-Derived Neurotrophic Factor / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology; D015870:Gene Expression / Q000502:physiology; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007395:Interneurons / Q000166:cytology* / Q000378:metabolism / Q000637:transplantation; D051379:Mice; D008810:Mice, Inbred C57BL; D019579:Neocortex / Q000166:cytology; D009410:Nerve Degeneration / Q000378:metabolism*; D009414:Nerve Growth Factors / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D018696:Neuroprotective Agents / Q000378:metabolism; D020933:Neurotrophin 3; D017966:Pyramidal Cells / Q000166:cytology*; D012333:RNA, Messenger / Q000032:analysis; D020794:Receptor Protein-Tyrosine Kinases / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D020801:Receptor, Ciliary Neurotrophic Factor; D017475:Receptors, Nerve Growth Factor / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000502:physiology
D019208:Brain-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D018696:Neuroprotective Agents; D020933:Neurotrophin 3; D012333:RNA, Messenger; D020801:Receptor, Ciliary Neurotrophic Factor; D017475:Receptors, Nerve Growth Factor; C071951:neurotrophin 5; D020794:Receptor Protein-Tyrosine Kinases; C073922:neurotrophin 4