Identification of a secreted BMP antagonist, ectodin, integrating BMP, FGF, and SHH signals from the tooth enamel knot
Identification of a secreted BMP antagonist, ectodin, integrating BMP, FGF, and SHH signals from the tooth enamel knot
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DOI：
10.1016/j.ydbio.2003.08.011
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发表时间：
2003-12-01
影响因子：
2.7
通讯作者：
Itoh, N
中科院分区：
文献类型：
--
作者：
Laurikkala, J;Kassai, Y;Itoh, N
我们已经确定了小鼠和人类的cDNA编码一种新的分泌型BMP抑制剂，我们命名为ectodin。它与分泌型BMP拮抗剂sclerostin同源性最高（相似于37%氨基酸同一性）。在培养的细胞中产生的重组ectodin蛋白作为拮抗剂被有效地分泌。Ectodin抑制小鼠前成骨细胞MC 3 T3-E1的BMP 2、BMP 4、BMP 6和BMP 7的活性，并以高亲和力与这些BMP结合。Ectodin在发育中的外胚层器官中强烈表达，包括牙齿、触须和毛囊。然而，它是缺席的头发基板和牙釉质结信号中心。此外，釉质结周围的几个细胞层是完全没有ectodin成绩单。分析了胞外多糖在牙胚发育中的调控作用。重组ectodin蛋白拮抗BMP介导的诱导Msx 2在培养的牙齿外植体的表达，表明ectodin是一种分泌型BMP抑制剂。BMP 2和BMP 7刺激了牙外植体中的ectodin表达，表明它是控制BMP活性的反馈机制的一部分。BMP刺激外泌素表达被SHH和FGF 4阻止，但Wnt 6不阻止。因此，BMP上调其自身抑制剂的反馈机制被釉结中与BMP共表达的信号抵消。我们的结论是，ectodin是一种新的BMP抑制剂，它整合了BMP信号与SHH和FGF信号通路，并有助于确定确切的时空域的BMP靶领域周围的外胚层信号中心。(C)2003年爱思唯尔公司All rights reserved.
We have identified mouse and human cDNAs encoding a novel secreted BMP inhibitor, which we have named ectodin. It is most homologous (similar to37% amino acid identity) to sclerostin that is a secreted BMP antagonist. Recombinant ectodin protein produced in cultured cells was efficiently secreted as a antagonist. Ectodin inhibited the activity of BMP2, BMP4, BMP6, and BMP7 for mouse preosteoblastic MC3T3-E1 cells, and bound to these BMPs with high affinity. Ectodin is intensely expressed in developing ectodermal organs, including teeth, vibrissae, and hair follicles. However, it is absent from the hair placodes and from the enamel knot signaling centers in teeth. In addition, several cell layers surrounding the enamel knots were completely devoid of ectodin transcripts. We analyzed the regulation and function of ectodin in tooth germs. Recombinant ectodin protein antagonized the BMP-mediated induction of Msx2 expression in cultured tooth explants, indicating that ectodin is a secreted BMP inhibitor. BMP2 and BMP7 stimulated ectodin expression in tooth explants, showing that it is part of a feedback mechanism controlling the activity of BMPs. The stimulation of ectodin expression by BMP was prevented by SHH and FGF4 but not by Wnt6. Hence, the feedback mechanism whereby BMPs upregulate their own inhibitor is counteracted by signals coexpressed with BMPs in the enamel knot. We conclude that ectodin is a novel BMP inhibitor which integrates BMP signaling with the SHH and FGF signal pathways and contributes in defining the exact spatiotemporal domain of BMP target field around the ectodermal signaling centers. (C) 2003 Elsevier Inc. All rights reserved.