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骨形态发生蛋白(BMP)通过诱导顶端外胚层嵴来控制脊椎动物肢体的近远轴生长以及背腹模式形成。

BMP controls proximodistal outgrowth, via induction of the apical ectodermal ridge, and dorsoventral patterning in the vertebrate limb.

作者信息

Pizette S, Abate-Shen C, Niswander L

机构信息

Molecular Biology Program and Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.

出版信息

Development. 2001 Nov;128(22):4463-74. doi: 10.1242/dev.128.22.4463.

Abstract

Dorsoventral (DV) patterning of the vertebrate limb requires the function of the transcription factor Engrailed 1 (EN1) in the ventral ectoderm. EN1 restricts, to the dorsal half of the limb, the expression of the two genes known to specify dorsal pattern. Limb growth along the proximodistal (PD) axis is controlled by the apical ectodermal ridge (AER), a specialized epithelium that forms at the distal junction between dorsal and ventral ectoderm. Using retroviral-mediated misexpression of the bone morphogenetic protein (BMP) antagonist Noggin or an activated form of the BMP receptor in the chick limb, we demonstrate that BMP plays a key role in both DV patterning and AER induction. Thus, the DV and PD axes are linked by a common signal. Loss and gain of BMP function experiments show that BMP signaling is both necessary and sufficient to regulate EN1 expression, and consequently DV patterning. Our results also indicate that BMPs are required during induction of the AER. Manipulation of BMP signaling results in either disruptions in the endogenous AER, leading to absent or severely truncated limbs or the formation of ectopic AERs that can direct outgrowth. Moreover, BMP controls the expression of the MSX transcription factors, and our results suggest that MSX acts downstream of BMP in AER induction. We propose that the BMP signal bifurcates at the level of EN1 and MSX to mediate differentially DV patterning and AER induction, respectively.

摘要

脊椎动物肢体的背腹(DV)模式形成需要转录因子Engrailed 1(EN1)在腹侧外胚层中发挥作用。EN1将已知指定背侧模式的两个基因的表达限制在肢体的背侧半部分。沿近远(PD)轴的肢体生长由顶端外胚层嵴(AER)控制,AER是一种特殊的上皮组织,形成于背侧和腹侧外胚层的远端交界处。通过逆转录病毒介导在鸡胚肢体中错误表达骨形态发生蛋白(BMP)拮抗剂Noggin或BMP受体的激活形式,我们证明BMP在DV模式形成和AER诱导中均起关键作用。因此,DV轴和PD轴由一个共同信号联系起来。BMP功能丧失和获得实验表明,BMP信号传导对于调节EN1表达以及进而调节DV模式形成是必要且充分的。我们的结果还表明,在AER诱导过程中需要BMP。对BMP信号传导的操纵导致内源性AER受到破坏,导致肢体缺失或严重截断,或者形成可指导生长的异位AER。此外,BMP控制MSX转录因子的表达,我们的结果表明MSX在AER诱导中作用于BMP的下游。我们提出,BMP信号在EN1和MSX水平分叉,分别介导不同的DV模式形成和AER诱导。

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