Extracellular signal-regulated protein kinase signaling is uncoupled from initial differentiation of central nervous system stem cells to neurons.

Knowledge about signaling pathways in response to external signals is needed to understand the regulation of stem cell proliferation and differentiation toward particular cell fates. The Ras/extracellular signal-regulated kinase (ERK) pathway has been suggested to play an essential role in neuronal differentiation. We have examined ERK signaling in the transition from multipotent stem cell to post-mitotic progeny using primary stem cells from the rat embryonic cortex. Fibroblast growth factor-2 (FGF-2) is a stem cell mitogen, whereas platelet-derived growth factor AA (PDGF-AA) expands a pool of committed neuronal precursors from stem cells. When comparing ERK activation by these growth factors, we found that FGF-2 stimulates high and PDGF-AA lower levels of ERK phosphorylation in stem cells. Differentiation was monitored as down-regulation of the bHLH transcription factor mammalian achaete-scute homologue-1 (MASH1). Even in the absence of active ERK, MASH1 became down-regulated and microtubule-associated protein 2-positive cells could form. Thus, ERK activation seems dispensable for the earliest steps of CNS stem cell differentiation.