Abstract
It has been shown that neural cell adhesion molecule (NCAM)-induced neuronal differentiation is extracellular signal-regulated kinase (ERK)-dependent. However, an involvement of the mitogen activated protein kinase (MAPK) kinase (MEK), an upstream kinase of ERK, has not been directly demonstrated in this process. Therefore, we investigated whether the MEK1 plays a critical role in the NCAM-induced neuronal differentiation of hippocampal neural progenitor cells (NPCs). NPCs were transiently transfected with expression plasmids encoding activated or dominant negative (DN) forms of MEK1. The expression of DN MEK1 inhibited neuronal phenotype acquisition and soluble NCAM rescued the defect in the neuronal phenotype acquisition in DN-MEK1-transfected cells, suggesting that NCAM might contribute to the neuronal differentiation via distinct, parallel pathways including the MEK pathway. In cells expressing wild type MEK1 or constitutively active MEK1 on the other hand, the percentage of cells positive for beta-tubulin type III (Tuj1), a marker for early postmitotic neurons, was higher than seen in vector-transfected cells. These results suggest that the activation of MEK1 is required for obtaining neuronal phenotype in NPCs.
Highlights
Neural cell adhesion molecule (NCAM) is a member of the immunoglobulin (Ig) superfamily and is involved in a variety of cellular processes of importance for the formation and maintenance of the nervous system
Two non-receptor tyrosine kinases, p59 fyn and the focal adhesion kinase, FAK, have been reported to interact with the 140-kDa isoform of NCAM (NCAM-140) (Beggs et al, 1994; 1997). In line with these findings, Kolkova et al could show that neurite outgrowth from PC12-E2 cells grown on substrata allowing homophilic NCAM interactions is dependent on the mitogen activated protein kinase (MAPK) pathway (Kolkova et al, 2000)
We previously demonstrated that soluble NCAM increased the differentiation of progenitor cells to the neuronal lineage with a concurrent upregulation of the proneural basic helix-loop-helix transcription factors, neurogenin1 and NeuroD (Shin et al, 2002)
Summary
Neural cell adhesion molecule (NCAM) is a member of the immunoglobulin (Ig) superfamily and is involved in a variety of cellular processes of importance for the formation and maintenance of the nervous system. Two non-receptor tyrosine kinases, p59 fyn and the focal adhesion kinase, FAK, have been reported to interact with the 140-kDa isoform of NCAM (NCAM-140) (Beggs et al, 1994; 1997). In line with these findings, Kolkova et al could show that neurite outgrowth from PC12-E2 cells grown on substrata allowing homophilic NCAM interactions is dependent on the MAPK pathway (Kolkova et al, 2000). We previously demonstrated that soluble NCAM increased the differentiation of progenitor cells to the neuronal lineage with a concurrent upregulation of the proneural basic helix-loop-helix (bHLH) transcription factors, neurogenin and NeuroD (Shin et al, 2002). Increase in homophilic NCAM binding either by soluble NCAM and overexpression of NCAM-140 is directly related to the activation of NCAM-dependent signaling pathways
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