Discrete endogenous signals mediate neural competence and induction in P19 embryonal carcinoma stem cells

Endogenous signals capable of inducing neuroectodermal differentiation are expressed by differentiating P19 EC cells in vitro. The present study demonstrates that at least two discrete signals are required. One is expressed by isolated primitive streak mesoderm-like cell lines and has the capacity to induce the expression of Pax-3 but, alone, induces neural differentiation inefficiently. The second signal is not expressed by the primitive streak mesoderm-like cell line but is present in conditioned media from differentiating P19 EC cells following DMSO treatment. This signal does not induce either Pax-3 expression or morphological differentiation and does not commit stem cells to a neuroectodermal fate. Rather, it acts synergistically with the signal derived from the primitive streak mesoderm-like cells to increase the efficiency with which stem cells respond initially by Pax-3 expression and subsequently by differentiation towards neural lineages. The activity of this second signal can be replaced by forskolin and 3-isobutyl-1-methyl-xanthine suggesting that its effects are transduced by a cyclic nucleotide-dependent pathway.