Wnt signal pathways and neural stem cell differentiation.

Self-renewal, migration and differentiation of neural progenitor cells are controlled by a variety of pleiotropic signal molecules. Members of the morphogen family of Wnt molecules play a crucial role for developmental and repair mechanisms in the embryonic and adult nervous system. A strategy of disclosure of the role of different canonical (glycogen synthase kinase-3beta/beta-catenin-dependent) and noncanonical (Ca2+- and JNK-dependent) signal pathways for progenitor cell expansion and differentiations is illustrated at the example of the rat striatal progenitor cell line ST14A that is immortalized by stable retroviral transfection with a temperature-sensitive mutant of the SV40 large T antigen. A shift from permissive 33 degrees C to nonpermissive 39 degrees C leads to proliferation stop and start of differentiation into glial and neuronal cells. Investigation of expression of Wnts, Wnt receptors and Wnt-dependent signal pathway assay point to a stage-dependent involvement of canonical and noncanonical signaling in proliferation and differentiation of ST14A cells, whereby a mutual suppression of pathway activities is likely. Canonical Wnt molecules are not detected in proliferating and differentiating ST14A cells except Wnt2. The noncanonical Wnt molecules Wnt4, Wnt5a and Wnt11 are expressed in proliferating cells and increase during differentiation, whereas cellular beta-catenin decreases in the early phase and is restored in the late phase of differentiation. Accumulation of beta-catenin at the membrane in undifferentiated proliferating cells and its nuclear localization in nondividing undifferentiated cells under differentiation conditions argues for a distinct spatially regulated role of the molecule in the proliferation and early differentiation phase. Ca2+-dependent and JNK-dependent noncanonical Wnt signaling is not detected during differentiation of ST14A cells. Complete exploration of the role of Wnt pathways, for differentiation of the neural progenitor cells ST14A will require Wnt overexpression and exposure of ST14A cells to exogenous Wnts either with purified Wnts or by co-cultures with Wnt producers. Copyright (c) 2006 S. Karger AG, Basel.