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First published online July 19, 2004
doi: 10.1242/10.1242/dev.01218
Department of Neurology, Northwestern University Feinberg School of Medicine, 303 East Chicago Avenue, Chicago, IL 60611, USA
* Authors for correspondence (e-mail: j-otero{at}northwestern.edu and jakessler{at}northwestern.edu)
Accepted 13 April 2004
Culture of embryonic stem (ES) cells at high density inhibits both ß-catenin signaling and neural differentiation. ES cell density does not influence ß-catenin expression, but a greater proportion of ß-catenin is targeted for degradation in high-density cultures. Moreover, in high-density cultures, ß-catenin is preferentially localized to the membrane further reducing ß-catenin signaling. Increasing ß-catenin signaling by treatment with Wnt3a-conditioned medium, by overexpression of ß-catenin, or by overexpression of a dominant-negative form of E-cadherin promotes neurogenesis. Furthermore, ß-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 ß-catenin. By contrast, RA does not induce neurogenesis in high-density cultures in the absence of ß-catenin signaling. Truncation of the armadillo domain of ß-catenin, but not the C terminus or the N terminus, eliminates its proneural effects. The proneural effects of ß-catenin reflect enhanced lineage commitment rather than proliferation of neural progenitor cells. Neurons induced by ß-catenin overexpression either alone or in association with RA express the caudal neuronal marker Hoxc4. However, RA treatment inhibits the ß-catenin-mediated generation of tyrosine hydroxylase-positive neurons, suggesting that not all of the effects of RA are dependent upon ß-catenin signaling. These observations suggest that ß-catenin signaling promotes neural lineage commitment by ES cells, and that ß-catenin signaling may be a necessary co-factor for RA-mediated neuronal differentiation. Further, enhancement of ß-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.
Key words: Embryonic stem cells, ß-Catenin, Neurogenesis, Retinoic acid, Tyrosine hydroxylase, Cell density
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