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Cell:肝脏发育研究获进展

2013-03-19 Huiqiang Lu 《细胞—发育》

近日来自中国西南大学生命科学学院的研究人员在新研究中证实,EpCAM作为一种内胚层特异性Wnt去阻抑子,促使了肝脏发育,相关论文“EpCAM Is an Endoderm-Specific Wnt Derepressor that Licenses Hepatic Development”发表在3月11日的《细胞—发育》(Developmental Cell)杂志上。 领导这一研究的是西南大学生

近日来自中国西南大学生命科学学院的研究人员在新研究中证实,EpCAM作为一种内胚层特异性Wnt去阻抑子,促使了肝脏发育,相关论文“EpCAM Is an Endoderm-Specific Wnt Derepressor that Licenses Hepatic Development”发表在3月11日的《细胞—发育》(Developmental Cell)杂志上。

领导这一研究的是西南大学生命科学学院教授、国家973重大科学研究计划“发育与生殖研究”领域项目首席科学家、两江学者罗凌飞(Lingfei Luo)。其主要研究方向为斑马鱼为模式动物,以内胚层组织器官及血管发育和再生的分子调控机制。曾获得2003年度德国马普协会主席-副主席创新奖(Gruss-J?ckle Prize,Innovation Prize),成为第一位也是迄今为止唯一一位获此奖项的中国人。

所有脊椎动物,包括人类在内,发育原理均极为相似,都是由内、中、外三个胚层进一步分化形成不同的组织和器官。内胚层主要发育成肝脏、胰腺、消化道、肺;中胚层则演变为躯干骨骼、肌肉、心脏、血管、血细胞等;外胚层则主要包括神经系统、表皮和头面骨骼。

肝脏、胰腺,是由内胚层发育而来的人体重要消化器官。然而迄今为止,不论体内还是体外,科学家们还无法有效人为诱导肝脏、胰腺、肠道细胞分化和再生。其中很重要的原因,是因为许多调控内胚层发育和再生的关键因子尚未被发现,或是已知因子的某些功能还有待发掘。内胚层组织器官发育和相关重大疾病防治,已成为当前发育与生殖领域的研究热点。

过去的研究发现在斑马鱼的发育阶段,Wnt2bb基因表达在两侧的侧板中胚层中。Wnt2bb这一由中胚层分泌的生长因子,能促进内胚层细胞进行肝脏的特化作用。因而在斑马鱼胚胎发育中,Wnt2bb信号传递调控了斑马鱼肝脏特化。

为了了解获得肝诱导Wnt2bb信号反应的机制,研究人员在斑马鱼中鉴定了一种内胚层丰富的单跨膜蛋白上皮细胞粘附分子(epithelial-cell-adhesion-molecule ,EpCAM),确定其是一种内胚层特异性Wnt去阻抑子。研究人员发现,hi2151/epcam突变体显示出与prt/wnt2bb相似的肝发育缺陷。机制研究证实,EpCAM直接与Kremen1结合,破坏了Kremen1-Dickkopf2 (Dkk2)互作,阻止了Kremen1-Dkk2介导从细胞表面除去脂蛋白受体相关蛋白6(LRP-6)。这些研究数据为研究人员提供了一个模型:即EpCAM使得Lrp6去抑制,协同Wnt配体通过稳定膜Lrp6,并使Lrp6在活化信号小体(signalosome)中聚集,激活了Wnt信号。因此,EpCAM细胞自主许可,并协同激活了内胚层细胞中的Wnt2bb信号。

研究结果表明EpCAM是一个重要的分子,它的功能机制赋予了内胚层细胞对肝诱导性Wnt2bb信号产生反应的能力。

肝脏相关的拓展阅读:

10.1016/j.devcel.2013.01.021
PMC:
PMID:

EpCAM Is an Endoderm-Specific Wnt Derepressor that Licenses Hepatic Development

Huiqiang Lu, Jun Ma, Yun Yang, Wenchao Shi, Lingfei Luo

Mechanisms underlying cell-type-specific response to morphogens or signaling molecules during embryonic development are poorly understood. To learn how response to the liver-inductive Wnt2bb signal is achieved, we identify an endoderm-enriched, single transmembrane protein, epithelial-cell-adhesion-molecule (EpCAM), as an endoderm-specific Wnt derepressor in zebrafish. hi2151/epcam mutants exhibit defective liver development similar to prt/wnt2bb mutants. EpCAM directly binds to Kremen1 and disrupts the Kremen1-Dickkopf2 (Dkk2) interaction, which prevents Kremen1-Dkk2-mediated removal of Lipoprotein-receptor-related protein 6 (Lrp6) from the cell surface. These data lead to a model in which EpCAM derepresses Lrp6 and cooperates with Wnt ligand to activate Wnt signaling through stabilizing membrane Lrp6 and allowing Lrp6 clustering into active signalosomes. Thus, EpCAM cell autonomously licenses and cooperatively activates Wnt2bb signaling in endodermal cells. Our results identify EpCAM as the key molecule and its functional mechanism to confer endodermal cells the competence to respond to the liver-inductive Wnt2bb signal.

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    2013-03-20 维他命
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    2013-03-21 neurowu

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