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First published online November 11, 2009
doi: 10.1242/10.1242/dev.036624

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Coordination of sonic hedgehog and Wnt signaling determines ventral and dorsal telencephalic neuron types from human embryonic stem cells

Xue-Jun Li^1,,, Xiaoqing Zhang^2,, M. Austin Johnson², Zhi-Bo Wang¹, Timothy LaVaute^2,* and Su-Chun Zhang²

¹ Department of Neuroscience, Stem Cell Institute, University of Connecticut Health Center, Farmington, CT 06030, USA
² Department of Anatomy and Department of Neurology, School of Medicine and Public Health, Waisman Center, University of Wisconsin-Madison, WI 53705, USA

Author for correspondence (xjli{at}uchc.edu)

Accepted September 25, 2009

The directed differentiation of forebrain neuronal types from human embryonic stem cells (hESCs) has not been achieved. Here, we show that hESCs differentiate to telencephalic progenitors with a predominantly dorsal identity in a chemically defined medium without known morphogens. This is attributed to endogenous Wnt signaling, which upregulates the truncated form of GLI3, a repressor of sonic hedgehog (SHH). A high concentration of SHH, or the inhibition of Wnt by dickkopf 1 (DKK1) together with a low concentration of SHH, almost completely converts the primitive dorsal precursors to ventral progenitors, which is partially achieved through both downregulation of the truncated GLI3 and upregulation of full-length GLI3 expression. These dorsal and ventral telencephalic progenitors differentiate to functional glutamatergic and GABAergic neurons, respectively. Thus, although hESCs generate dorsal telencephalic cells, as opposed to ventral progenitors in other vertebrates, in the absence of exogenous morphogens, human cells use a similar molecular mechanism to control the dorsal versus ventral fate. The coordination of Wnt and SHH signaling through GLI3 represents a novel mechanism that regulates ventral-dorsal patterning in the development of forebrain neuronal subtypes.

Key words: Human embryonic stem cells, Neural patterning, Neural differentiation, Sonic hedgehog, Wnt signaling

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