Postnatal cerebral cortical multipotent progenitors: Regulatory mechanismsand potential role in the development of novel neural regenerative strategies

In the developing postnatal cerebral cortex, protracted generation of glia and neurons occurs and precise matching of local cell types is needed for t he functional organization of regional microdomains characteristic of compl ex CNS tissues. Recent studies have suggested that multipotent progenitors play an important role in neural lineage elaboration during neurogenesis an d gliogenesis after migration from paramedian generative zones,The presence of a separate reservoir of cerebral cortical multipotent cells under stric t local environmental regulation would provide an appropriate mechanism for terminal developmental sculpting and for reconstitution of regional cellul ar pools after injury. We have isolated distinct pools of EGF- and bFGF-res ponsive multipotent progenitors from the postnatal mammalian cerebral corte x independent of the subventricular zone. These progenitor populations are under tight environmental regulation by specific hierarchies of cytokine su bclasses that program the progressive elaboration of intermediate lineage-r estricted progenitors and differentiated type I and II astrocytes, myelinat ing oligodendrocytes and neuronal subtypes that express specific neuromodul atory proteins. Neural lineage development from these cortical multipotent progenitors is a graded developmental process involving sequential inductio n of specific cytokine receptors, acquisition of factor responsiveness and complex lineage interdependence. The cortical multipotent progenitor pathwa ys program the elaboration of neural lineage species with distinct cellular response properties when compared with analogous species derived from subv entricular zone progenitors, indicating that the cortical multipotent cells contribute to the establishment of lineage diversity within the developing cortical cortex, In addition, the cortical multipotent cells generate dyna mic intermediate progenitor pools that utilize temporally- coded environmen tal cues to alter neural fate decisions. These cumulative observations sugg est that postnatal cerebral cortical multipotent cells represent a novel se t of progenitor pathways necessary for normal mammalian cortical maturation , and may have important implications for our understanding of a wide varie ty of neuropathological conditions and for the development of more effectiv e regenerative strategies to combat these pervasive neurological disorders.