Kremen proteins interact with Dickkopf1 to regulate anteroposterior CNS patterning
Kremen proteins interact with Dickkopf1 to regulate anteroposterior CNS patterning
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DOI：
10.1242/dev.00154
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发表时间：
2002-12-01
期刊：
影响因子：
4.6
通讯作者：
Niehrs, C
中科院分区：
文献类型：
--
作者：
Davidson, G;Mao, BY;Niehrs, C
在非洲爪蟾原肠胚形成过程中，后向Wnt和前向Wnt拮抗剂形成的Wnt/ β -连环蛋白信号梯度调节中枢神经系统（CNS）的前后（AP）模式。在这一过程中，分泌的Wnt拮抗剂Dkk1通过阻断脂蛋白受体相关蛋白（LRP） 5类和6类的Wnt受体，在Spemann组织者及其前衍生物中发挥作用。除了LRP6外，Dkk1还与最近发现的另一类受体——跨膜蛋白Kremen1 （Krm1）和Kremen2 （Krm2）相互作用，协同抑制LRP6。我们研究了Krm1和Krm2在爪蟾早期胚胎发生中的作用。与在合子Wnt抑制中的作用一致，过表达的Krm使胚胎前化并挽救被Wnt8后化的胚胎。反义morpholino oligonucleotide （Mo）敲低Krm1和Krm2导致前神经发育缺陷。在这一过程中，Krm蛋白与Dkk1相互作用：(1)在轴复制实验中，krm2与Dkk1协同抑制Wnt/LRP6信号传导；(2) krm2可挽救注射抑制抗dkk1抗体诱导的小头畸形胚胎；(3)注射krm1/2反义Mo可增强抑制性抗dkk1抗体诱导的小头畸形。结果表明，Krm蛋白在Wnt抑制通路中发挥作用，调节中枢神经系统早期AP模式。
A gradient of Wnt/beta-catenin signalling formed by posteriorising Wnts and anteriorising Wnt antagonists regulates anteroposterior (AP) patterning of the central nervous system (CNS) during Xenopus gastrulation. In this process, the secreted Wnt antagonist Dkk1 functions in the Spemann organiser and its anterior derivatives by blocking Wnt receptors of the lipoprotein receptor-related protein (LRP) 5 and 6 class. In addition to LRP6, Dkk1 interacts with another recently identified receptor class, the transmembrane proteins Kremen1 (Krm1) and Kremen2 (Krm2) to synergistically inhibit LRP6. We have investigated the role of Krm1 and Krm2 during early Xenopus embryogenesis. Consistent with a role in zygotic Wnt inhibition, overexpressed Krm anteriorises embryos and rescues embryos posteriorised by Wnt8. Antisense morpholino oligonucleotide (Mo) knockdown of Krm1 and Krm2 leads to deficiency of anterior neural development. In this process, Krm proteins functionally interact with Dkk1: (1) in axis duplication assays krm2 synergises with dkk1 in inhibiting Wnt/LRP6 signalling; (2) krm2 rescues microcephalic embryos induced by injection of inhibitory anti-Dkk1 antibodies; and (3) injection of krm1/2 antisense Mo enhances microcephaly induced by inhibitory anti-Dkk1 antibodies. The results indicate that Krm proteins function in a Wnt inhibition pathway regulating early AP patterning of the CNS.