Soluble Jagged1 Attenuates Lateral Inhibition Allowing for the Clonal Expansion of Neural Crest Stem Cells

¹ Centers for Molecular and Regenerative Medicine, Maine Medical Center Research Institute, 81 Research Drive, Scarborough, Maine 04074
² Interdisciplinary Program in Molecular Genetics and Cell Biology, University of Maine, 535 Hitchner Hall, Orono, ME, 04469-5737
³ Centers for Molecular and Regenerative Medicine, Maine Medical Center Research Institute, 81 Research Drive, Scarborough, Maine 04074, Interdisciplinary Program in Molecular Genetics and Cell Biology, University of Maine, 535 Hitchner Hall, Orono, ME, 04469-5737

^* To whom correspondence should be addressed. E-mail: verdij{at}mmc.org.

	Abstract

The activation of Notch signaling in neural crest stem cells (NCSC) results in the rapid loss of neurogenic potential and differentiation into glia. We now show that the attenuation of endogenous Notch signaling within expanding NCSC clones by the soluble Notch ligand, Jagged1 (sJ1), maintains NCSCs in a clonal self-renewing state in vitro without affecting their sensitivity to instructive differentiation signals observed previously during NCSC self-renewal. sJ1 functions as a competitive inhibitor of Notch signaling to modulate endogenous cell: cell communication to levels sufficient to inhibit neural differentiation but insufficient to instruct gliogenic differentiation. Attenuated Notch signaling promotes the induction and non-classical release of FGF1. The functions of sJ1 and FGF1 signaling are complementary as abrogation of FGF signaling diminishes the ability of sJ1 to promote NCSC expansion, yet the secondary NCSCs maintain the dosage sensitivity of the founder. These results validate and build upon previous studies on the role of Notch-signaling in stem cell self-renewal and suggest that the differentiation bias or self-renewal potential of NCSCs is intrinsically linked to the level of endogenous Notch signaling. This should provide a unique opportunity for the expansion of NCSCs ex vivo without altering their differentiation bias for clinical cell replacement or transplant strategies in tissue repair.

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