Heterodimeric TGF-β ligands outperform homodimers in a variety of developmental, cell culture, and therapeutic contexts; however, the mechanisms underlying this increased potency remain uncharacterized. Here, we use dorsal–ventral axial patterning of the zebrafish embryo to interrogate the BMP2/7 heterodimer signaling mechanism. We demonstrate that differential interactions with BMP antagonists do not account for the reduced signaling ability of homodimers. Instead, we find that while overexpressed BMP2 homodimers can signal, they require two nonredundant type I receptors, one from the Acvr1 subfamily and one from the Bmpr1 subfamily. This implies that all BMP signaling within the zebrafish gastrula, even BMP2 homodimer signaling, requires Acvr1. This is particularly surprising as BMP2 homodimers do not bind Acvr1 in vitro. Furthermore, we find that the roles of the two type I receptors are subfunctionalized within the heterodimer signaling complex, with the kinase activity of Acvr1 being essential, while that of Bmpr1 is not. These results suggest that the potency of the Bmp2/7 heterodimer arises from the ability to recruit both Acvr1 and Bmpr1 into the same signaling complex.

在各种发育，细胞培养和治疗方面，异二聚体TGF-β配体的性能均优于同二聚体。然而，这种增强效力的潜在机制仍未阐明。在这里，我们使用斑马鱼胚胎的背-腹轴向模式来询问BMP2 / 7异二聚体信号传导机制。我们证明与BMP拮抗剂的差异相互作用不能解释同二聚体的信号传导能力降低。相反，我们发现虽然过表达的BMP2同型二聚体可以发出信号，但它们需要两种非冗余的I型受体，一种来自Acvr1亚家族，另一种来自Bmpr1亚家族。这意味着斑马鱼腹腔内的所有BMP信号，甚至BMP2同型二聚体信号，都需要Acvr1。这尤其令人惊讶，因为BMP2同型二聚体在体外不结合Acvr1。此外，我们发现这两种I型受体的作用在异二聚体信号传导复合物中是亚功能化的，其中Acvr1的激酶活性是必不可少的，而Bmpr1的激酶活性则不是必需的。这些结果表明Bmp2 / 7异二聚体的效力源于将Acvr1和Bmpr1募集到同一信号复合物中的能力。