The evolution of a new cell type was associated with competition for a signaling ligand

There is presently a very limited understanding of the mechanisms that underlie the evolution of new cell types. The skeleton-forming primary mesenchyme cells (PMCs) of euechinoid sea urchins, derived from the micromeres of the 16-cell embryo, are an example of a recently evolved cell type. All adult echinoderms have a calcite-based endoskeleton, a synapomorphy of the Ambulacraria. Only euechinoids have a micromere-PMC lineage, however, which evolved through the co-option of the adult skeletogenic program into the embryo. During normal development, PMCs alone secrete the embryonic skeleton. Other mesoderm cells, known as blastocoelar cells (BCs), have the potential to produce a skeleton, but a PMC-derived signal ordinarily prevents these cells from expressing a skeletogenic fate and directs them into an alternative developmental pathway. Recently, it was shown that vascular endothelial growth factor (VEGF) signaling plays an important role in PMC differentiation and is part of a conserved program of skeletogenesis among echinoderms. Here, we report that VEGF signaling, acting through ectoderm-derived VEGF3 and its cognate receptor, VEGF receptor (VEGFR)-10-Ig, is also essential for the deployment of the skeletogenic program in BCs. This VEGF-dependent program includes the activation of aristaless-like homeobox 1 (alx1), a conserved transcriptional regulator of skeletogenic specification across echinoderms and an example of a “terminal selector” gene that controls cell identity. We show that PMCs control BC fate by sequestering VEGF3, thereby preventing activation of alx1 and the downstream skeletogenic network in BCs. Our findings provide an example of the regulation of early embryonic cell fates by direct competition for a secreted signaling ligand, a developmental mechanism that has not been widely recognized. Moreover, they reveal that a novel cell type evolved by outcompeting other embryonic cell lineages for an essential signaling ligand that regulates the expression of a gene controlling cell identity.目前学界对新型细胞类型演化的核心分子机制仍缺乏深入认知。真海胆类（euechinoid）海胆的成骨型初级间充质细胞（primary mesenchyme cells, PMCs）起源于16细胞期胚胎的小裂球，便是一类新近演化形成的细胞类型的典型范例。所有成年棘皮动物均拥有方解石型内骨骼，这是步带动物类群（Ambulacraria）的共有衍征。但仅有真海胆类拥有小裂球-PMC谱系，该谱系通过将成体成骨程序共选择至胚胎发育过程中演化而来。在正常发育过程中，仅PMCs会分泌胚胎骨骼。另一类中胚层细胞——胚腔细胞（blastocoelar cells, BCs）虽具备产生骨骼的潜能，但PMCs分泌的信号通常会抑制这些细胞的成骨命运，并引导其进入另一发育通路。 此前已有研究表明，血管内皮生长因子（vascular endothelial growth factor, VEGF）信号通路在PMC分化中发挥关键作用，且是棘皮动物中成骨程序的保守调控通路之一。本研究发现，由外胚层来源的VEGF3及其同源受体VEGF受体（VEGF receptor, VEGFR）-10-Ig介导的VEGF信号通路，同样对BCs中成骨程序的激活至关重要。这一依赖VEGF的调控程序包括激活无翅类同源框1（aristaless-like homeobox 1, alx1）——这是一种在棘皮动物中保守的成骨特化转录调控因子，同时也是一类调控细胞身份的"终端选择基因"。 我们的研究证实，PMCs通过螯合VEGF3来控制BCs的细胞命运，从而阻断alx1及下游成骨网络在BCs中的激活。本研究揭示了一种通过直接竞争分泌型信号配体来调控早期胚胎细胞命运的发育机制，这类机制此前尚未被广泛认知。此外，本研究还表明，新型细胞类型的演化可通过竞争获取调控细胞身份基因表达的必需信号配体，从而击败其他胚胎细胞谱系而实现。