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

被引:241
|
作者
Li, Xue-Jun [1 ]
Zhang, Xiaoqing [2 ,3 ]
Johnson, M. Austin [2 ,3 ]
Wang, Zhi-Bo [1 ]
LaVaute, Timothy [2 ,3 ]
Zhang, Su-Chun [2 ,3 ]
机构
[1] Univ Connecticut, Ctr Hlth, Dept Neurosci, Stem Cell Inst, Farmington, CT 06030 USA
[2] Univ Wisconsin, Dept Anat, Madison, WI 53705 USA
[3] Univ Wisconsin, Dept Neurol, Sch Med & Publ Hlth, Waisman Ctr, Madison, WI 53705 USA
来源
DEVELOPMENT | 2009年 / 136卷 / 23期
基金
美国国家卫生研究院;
关键词
Human embryonic stem cells; Neural patterning; Neural differentiation; Sonic hedgehog; Wnt signaling; STRIATAL PROJECTION NEURONS; DIRECTED DIFFERENTIATION; ACTIVATOR FUNCTION; SPECIFICATION; GLI3; PRECURSORS; REPRESSOR; SHH; SUBTYPES; GENES;
D O I
10.1242/dev.036624
中图分类号
Q [生物科学];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
引用
收藏
页码:4055 / 4063
页数:9
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