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.

异二聚体 TGF-β 配体在各种发育、细胞培养和治疗环境中优于同二聚体；然而，这种增加效力的机制仍未确定。在这里，我们使用斑马鱼胚胎的背腹轴向模式来询问 BMP2/7 异二聚体信号机制。我们证明了与 BMP 拮抗剂的不同相互作用不能解释同源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 同源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。这意味着斑马鱼原肠胚中的所有 BMP 信号，甚至 BMP2 同源二聚体信号，都需要 Acvr1。这尤其令人惊讶，因为 BMP2 同源二聚体在体外不结合 Acvr1。此外，我们发现两种 I 型受体的作用在异二聚体信号复合体中被亚功能化，其中 Acvr1 的激酶活性是必不可少的，而 Bmpr1 则不是。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体中的能力。