Sequential specification of neurons and glia by developmentally regulated extracellular factors

Cortical progenitor cells give rise to neurons during embryonic development and to glia after birth. While lineage studies indicate that multipotent p rogenitor cells are capable of generating both neurons and glia, the role o f extracellular signals in regulating the sequential differentiation of the se cells is poorly understood. To investigate how factors in the developing cortex might influence cell fate, we developed a cortical slice overlay as say in which cortical progenitor cells are cultured over cortical slices fr om different developmental stages. We find that embryonic cortical progenit ors cultured over embryonic cortical slices differentiate into neurons and those cultured over postnatal cortical slices differentiate into glia, sugg esting that the fate of embryonic progenitors can be influenced by developm entally regulated signals. In contrast, postnatal progenitor cells differen tiate into glial cells when cultured over either embryonic or postnatal cor tical slices. Clonal analysis indicates that the postnatal cortex produces a diffusible factor that induces progenitor cells to adopt glial fates at t he expense of neuronal fates. The effects of the postnatal cortical signals on glial cell differentiation are mimicked by FGF2 and CNTF, which induce glial fate specification and terminal glial differentiation respectively. T hese observations indicate that cell fate specification and terminal differ entiation can be independently regulated and suggest that the sequential ge neration of neurons and glia in the cortex is regulated by a developmental increase in gliogenic signals.