R-spondin2 expression in the apical ectodermal ridge is essential for outgrowth and patterning in mouse limb development
R-spondin2 expression in the apical ectodermal ridge is essential for outgrowth and patterning in mouse limb development
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DOI：
10.1111/j.1440-169x.2007.00978.x
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发表时间：
2008-02-01
影响因子：
2.5
通讯作者：
Okamoto, Hitoshi
中科院分区：
文献类型：
--
作者：
Aoki, Motoko;Kiyonari, Hiroshi;Okamoto, Hitoshi
小鼠R-spondin 2（Rspo 2）是R-spondin蛋白家族的成员，其特征在于富含弗林蛋白酶样半胱氨酸的结构域和血小板反应蛋白1型重复。R-spondin是一种激活Wnt/β-连环蛋白信号传导的分泌分子。产生Rspo 2缺陷小鼠以研究小鼠Rspo 2在胚胎发育期间的功能。纯合子突变前肢远端趾骨和指甲结构存在缺陷，手指形状异常。纯合子突变后肢表现出更严重的畸形，包括缺乏数字和zeugopod组件。Rspo 2在发育肢体的顶端外胚层嵴（AER）中表达。Fgf 8在AER中的表达在纯合突变前肢中显著低于野生型前肢，并且沿背腹轴沿着受到干扰。在纯合子突变后肢，Fgf 8和Fgf 4的表达后AER和Sonic刺猬表达的极化活动区（ZPA）减少。纯合突变后肢也表现出扩大Wnt 7a表达的背侧外胚层向腹侧。这项研究表明，Rspo 2对维持AER以及肢体发育中的生长和模式至关重要。
Mouse R-spondin2 (Rspo2) is a member of the R-spondin protein family, which is characterized by furin-like cysteine-rich domains and a thrombospondin type 1 repeat. R-spondin is a secreted molecule that activates Wnt/beta-catenin signaling. Rspo2-deficient mice were generated to investigate the function of mouse Rspo2 during embryonic development. The homozygous mutant forelimb showed defects in distal phalanges and nail structures, and the digits were anomalous in shape. The homozygous mutant hindlimb showed more severe malformations, including lack of digits and zeugopod components. Rspo2 is expressed in the apical ectodermal ridge (AER) of the developing limb. Fgf8 expression in the AER was significantly lower in the homozygous mutant forelimb than in the wild-type forelimb and it was disturbed along the dorsoventral axis. In the homozygous mutant hindlimb, Fgf8 and Fgf4 expression in the posterior AER and Sonic hedgehog expression in the zone of polarizing activity (ZPA) were reduced. The homozygous mutant hindlimb also showed expansion of Wnt7a expression in the dorsal ectoderm toward the ventral side. This study shows that Rspo2 is critical for maintenance of the AER and for growth and patterning in limb development.