β-catenin signaling is required for neural diffrerentiation of embryonic stem cells

José Javier Otero*, Weimin Fu, Lixin Kan, Adolfo E. Cuadra, John A. Kessler

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

159 Scopus citations

Abstract

Culture of embryonic stem (ES) cells at high density inhibits both β-catenin signaling and neural differentiation. ES cell density does not influence β-catenin expression, but a greater proportion of β-catenin is targeted for degradation in high-density cultures. Moreover, in high-density cultures, β-catenin is preferentially localized to the membrane further reducing β-catenin signaling. Increasing β-catenin signaling by treatment with Wnt3a-conditioned medium, by overexpression of β-catenin, or by overexpression of a dominant-negative form of β-cadherin promotes neurogenesis. Furthermore, β-catenin signaling is sufficient to induce neurogenesis in high-density cultures even in the absence of retinoic acid (RA), although RA potentiates the effects of β-catenin. By contrast, RA does not induce neurogenesis in high-density cultures in the absence of β-catenin signaling. Truncation of the armadillo domain of β-catenin, but not the C terminus or the N terminus, eliminates its proneural effects. The proneural effects of β -catenin reflect enhanced lineage commitment rather than proliferation of neural progenitor cells. Neurons induced by β-catenin overexpression either alone or in association with RA express the caudal neuronal marker Hoxc4. However, RA treatment inhibits the β -catenin-mediated generation of tyrosine hydroxylase-positive neurons, suggesting that not all of the effects of RA are dependent upon β -catenin signaling. These observations suggest that β-catenin signaling promotes neural lineage commitment by ES cells, and that β -catenin signaling may be a necessary co-factor for RA-mediated neuronal differentiation. Further, enhancement of β-catenin signaling with RA treatment significantly increases the numbers of neurons generated from ES cells, thus suggesting a method for obtaining large numbers of neural species for possible use in for ES cell transplantation.

Original languageEnglish (US)
Pages (from-to)3545-3557
Number of pages13
JournalDevelopment
Volume131
Issue number15
DOIs
StatePublished - Aug 2004

Keywords

  • Cell density
  • Embryonic stem cells
  • Neurogenesis
  • Retinoic acid
  • Tyrosine hydroxylase
  • β-catenin

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology

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