Stabilized β-Catenin Functions through TCF/LEF Proteins and the Notch/RBP-Jκ Complex To Promote Proliferation and Suppress Differentiation of Neural Precursor Cells

Abstract

The proliferation and differentiation of neural precursor cells are mutually exclusive during brain development. Despite its importance for precursor cell self renewal, the molecular linkage between these two events has remained unclear. Fibroblast growth factor 2 (FGF2) promotes neural precursor cell proliferation and concurrently inhibits their differentiation, suggesting a cross talk between proliferation and differentiation signaling pathways downstream of the FGF receptor. We demonstrate that FGF2 signaling through phosphatidylinositol 3 kinase activation inactivates glycogen synthase kinase 3␤ (GSK3␤) and leads to the accumulation of ␤-catenin in a manner different from that in the Wnt canonical pathway. The nuclear accumulated ␤-catenin leads to cell proliferation by activating LEF/TCF transcription factors and concurrently inhibits neuronal differentiation by potentiating the Notch1-RBP-J signaling pathway. ␤-Catenin and the Notch1 intracellular domain form a molecular complex with the promoter region of the antineurogenic hes1 gene, allowing its expression. This signaling interplay is especially essential for neural stem cell maintenance, since the misexpression of dominant-active GSK3␤ completely inhibits the self renewal of neurosphere-forming stem cells and prompts their neuronal differentiation. Thus, the GSK3␤/␤-catenin signaling axis regulated by FGF and Wnt signals plays a pivotal role in the maintenance of neural stem/precursor cells by linking the cell proliferation to the inhibition of differentiation.

Hes1: a key role in stemness, metastasis and multidrug resistance

“…b-catenin, a downstream factor of Wnt signaling, increases Hes1 expression by binding with NICD and stabilizes the CSL-NICD complex by recruiting p300 and P/CAF. [75][76][77] HIF-1 is required to promote interactions with NICD and potentiate the stabilization of the CSL-NICD complex under hypoxia conditions, while induction of Hes1 protects progenitor cells, as well as tumor stem cells, against differentiation. [78][79][80][81] Non-canonical Notch signaling pathway Notch signaling pathway can exert its biological function independently of its ligands, receptors or CSL in vertebrates.…”

The Leukemia-associated Mll-Ell Oncoprotein Induces Fibroblast Growth Factor 2 (Fgf2)-dependent Cytokine Hypersensitivity in Myeloid Progenitor Cells

“…In myeloid progenitor cells, Fgf2 binding to Fgf-R1/R2 activates phosphoinositol 3-kinase (31,32). Phosphoinositol 3-kinase activates Akt kinase, which inhibits glycogen synthase kinase 3␤.…”

Androgens Up-regulate Transcription of the Notch Inhibitor Numb in C2C12 Myoblasts via Wnt/β-Catenin Signaling to T Cell Factor Elements in the Numb Promoter

“…Accumulating evidence has underlined the importance of the mutually inhibitory cross-talk between Wnt and Notch pathways (11)(12)(13)(14)(15)(16)(43)(44)(45). In injured skeletal muscle, Notch and Wnt exert opposing influences on proliferation and differentiation of progenitor cells, respectively, as illustrated in studies by Brack et al using cultured muscle satellite cells (4).…”

“…Wnt and Notch signaling configure an integrated molecular device whose main function is to regulate transitions between cell states in development and homeostasis (11)(12)(13)(14)(15)(16) (17,18). Numb inhibits Notch activity by targeting Notch and Notch intracellular domain for proteolytic degradation (19).…”