BMP7 functions predominantly as a heterodimer with BMP2 or BMP4 during mammalian embryoaenesis
BMP7 functions predominantly as a heterodimer with BMP2 or BMP4 during mammalian embryoaenesis
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DOI：
10.7554/elife.48872
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发表时间：
2019-09-30
期刊：
影响因子：
7.7
通讯作者：
Christian, Jan L.
中科院分区：
文献类型：
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作者：
Kim, Hyung-Seok;Neugebauer, Judith;Christian, Jan L.
BMP 7/BMP 2或BMP 7/BMP 4异二聚体在体外比同二聚体更有活性，但不知道这些异二聚体是否在体内发出信号。为了测试这一点，我们在携带突变（Bmp 7（R-GFlag））的小鼠中产生敲除，所述突变防止二聚化BMP 7前体蛋白的蛋白水解活化。这种突变消除了BMP 7同源二聚体和所有其他通常与BMP 7异源二聚体化的BMP的功能。虽然Bmp 7无效纯合子是活产的，但Bmp 7（R-GFlag）纯合子是胚胎致死的并且具有广泛降低的BMP活性。此外，携带Bmp 7（R-G）等位基因以及Bmp 2或Bmp 4的无效等位基因的复合杂合子在胚胎发生期间死亡，具有腹体壁闭合和/或心脏的缺陷。免疫共沉淀试验证实存在内源性BMP 4/7异二聚体。因此，在哺乳动物发育过程中，BMP 7主要作为BMP 2或BMP 4的异二聚体发挥作用，这可以解释为什么Bmp 4或Bmp 7中的突变导致人类中类似的先天性缺陷谱。
BMP7/BMP2 or BMP7/BMP4 heterodimers are more active than homodimers in vitro, but it is not known whether these heterodimers signal in vivo. To test this, we generated knock in mice carrying a mutation (Bmp7(R-GFlag)) that prevents proteolytic activation of the dimerized BMP7 precursor protein. This mutation eliminates the function of BMP7 homodimers and all other BMPs that normally heterodimerize with BMP7. While Bmp7 null homozygotes are live born, Bmp7(R-GFlag) homozygotes are embryonic lethal and have broadly reduced BMP activity. Furthermore, compound heterozygotes carrying the Bmp7(R-G) allele together with a null allele of Bmp2 or Bmp4 die during embryogenesis with defects in ventral body wall closure and/or the heart. Co-immunoprecipitation assays confirm that endogenous BMP4/7 heterodimers exist. Thus, BMP7 functions predominantly as a heterodimer with BMP2 or BMP4 during mammalian development, which may explain why mutations in either Bmp4 or Bmp7 lead to a similar spectrum of congenital defects in humans.