Specific neurotrophic factors support the survival of cortical projection neurons at distinct stages of development

Repair of specific neuronal circuitry in the neocortex may be possible via neural precursor transplantation or manipulation of endogenous precursors in situ. These approaches will almost certainly require a detailed understanding of the mechanisms that control survival and differentiation of specific neuronal lineages. Such analysis has been hampered by the overwhelming diversity of neuronal types intermixed in neocortex and the inability to isolate individual lineages. To elucidate stage-specific controls over the survival of individual lineages of cortical neurons, we purified immature callosal projection neurons (CPN) at distinct stages of development from embryonic and postnatal mouse cortex by retrograde fluorescence labeling, followed by fluorescence-activated cell sorting. Purified CPN survive well in culture, acquire stage-specific projection neuron morphologies, and express appropriate neurotransmitters and growth factor receptors. Purified CPN are dependent on exogenous trophic support for survival in a stage-specific manner. Survival of postnatal day 2 (P2) to P3 and P6-P7 CPN is promoted by overlapping but distinct sets of neurotrophic factors, whereas embryonic day 19 CPN show less specificity of dependence on peptide factors. These studies demonstrate for the first time the stage-specific control by peptide growth factors over the survival of a specific cortical neuronal lineage. Such information may be critical for the future goal of directed differentiation of transplanted or endogenous precursors toward cellular repair of complex cortical circuitry.