Patterning of the dorsal-ventral axis in echinoderms: insights into the evolution of the BMP-chordin signaling network.
Patterning of the dorsal-ventral axis in echinoderms: insights into the evolution of the BMP-chordin signaling network.
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DOI：
10.1371/journal.pbio.1000248
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发表时间：
2009-11
期刊：
影响因子：
9.8
通讯作者：
Lepage T
中科院分区：
文献类型：
--
作者：
Lapraz F;Besnardeau L;Lepage T
破译海胆背腹模式的过程揭示了 BMP 易位的极端情况以及棘皮动物中 BMP-脊索蛋白轴的不寻常配置。海胆胚胎背腹轴的形成依赖于 TGFβ 节点引发的细胞相互作用。有趣的是，虽然 nodal 表达仅限于胚胎的腹侧，但 nodal 功能是腹侧和背侧区域规范所必需的，并且能够恢复 nodal 吗啉代注射胚胎中的腹侧和背侧区域。 Nodal 的远程组织活性的分子基础尚不清楚。在本文中，我们提供的证据表明，Nodal 的远程组织活性是由腹侧外胚层中合成的中继分子保证的，然后转移到胚胎的另一侧。我们基于以下论点将该中继分子鉴定为 BMP2/4。首先，在轴救援试验中，阻断 BMP2/4 功能消除了激活的 Nodal 受体的长程组织活性。其次，我们证明 BMP2/4 和相应的 I 型受体 Alk3/6 功能对于胚胎背部区域的规范都是必需的。第三，使用抗磷酸化Smad1/5/8免疫染色，我们发现，尽管BMP2/4配体在腹侧转录，但它仅在胚胎的背侧触发受体介导的信号传导，这是迄今为止描述的最极端的BMP易位案例之一。我们进一步报道，pSmad1/5/8 的模式沿着背腹轴分级，并且两个 BMP2/4 靶基因以以 pSmad1/5/8 水平最高的区域为中心的嵌套模式表达，强烈表明 BMP2/4 充当形态发生素。我们还描述了Nodal下游的chordin和bmp2/4非常不寻常的腹侧共表达，并证明Chordin在很大程度上负责BMP2/4信号传导到背侧的空间限制。因此，与大多数生物体不同，在海胆中，单个腹侧信号中心负责诱导腹侧和背侧细胞的命运。最后，我们证明 BMP2/4 的长距离扩散可能不需要 Chordin，描述了磷脂酰肌醇蛋白聚糖 5（一种调节 BMP 迁移性的肝素硫酸化蛋白聚糖）表达中显着的背腹不对称性，并表明这种不对称性取决于 BMP2/4 信号传导。我们的研究为沿着海胆胚胎的背腹轴建立位置信息的机制提供了新的见解，更一般地说，为如何在多细胞胚胎中建立 BMP 形态发生素梯度提供了新的见解。从进化的角度来看，它强调虽然用于背腹模式形成的基因在两侧对称动物中高度保守，但即使在后口动物中，这些基因用于形成 BMP 形态发生素梯度的方式也存在相当大的差异。在许多生物体的早期发育过程中，沿背腹轴的模式由位于胚胎腹侧和背侧的两个信号中心的活动调节。其中一个中心产生 BMP 家族的生长因子，充当形态发生素，而另一个中心则分泌 BMP 拮抗剂，例如调节 BMP 沿背腹轴流动的 Chordin。这两个信号中心的表达导致 BMP 和 BMP 拮抗剂的分布大致互补。我们分析了海胆胚胎中 BMP 介导的背腹轴模式，海胆在系统发育上与脊椎动物接近，并且其发育广泛依赖于细胞与细胞的相互作用。我们发现，与大多数生物体不同，海胆腹侧的单个信号中心的活动负责产生胚胎的腹侧和背侧。此外，我们发现 BMP2/4 基因与腹侧中心的脊索蛋白共表达，但 BMP2/4 蛋白易位到胚胎的另一侧，激活负责背侧分化的遗传程序。我们的研究揭示了 BMP 生长因子远距离信号传导的一个不寻常的例子。它还强调，尽管用于背腹模式形成的蛋白质在进化上是保守的，但这些蛋白质在不同物种中用于产生 BMP 形态发生素梯度的方式存在相当大的差异。
Deciphering the process of dorsal-ventral patterning in the sea urchin reveals an extreme case of BMP translocation and an unusual configuration of the BMP-Chordin axis in echinoderms. Formation of the dorsal-ventral axis of the sea urchin embryo relies on cell interactions initiated by the TGFβ Nodal. Intriguingly, although nodal expression is restricted to the ventral side of the embryo, Nodal function is required for specification of both the ventral and the dorsal territories and is able to restore both ventral and dorsal regions in nodal morpholino injected embryos. The molecular basis for the long-range organizing activity of Nodal is not understood. In this paper, we provide evidence that the long-range organizing activity of Nodal is assured by a relay molecule synthesized in the ventral ectoderm, then translocated to the opposite side of the embryo. We identified this relay molecule as BMP2/4 based on the following arguments. First, blocking BMP2/4 function eliminated the long-range organizing activity of an activated Nodal receptor in an axis rescue assay. Second, we demonstrate that BMP2/4 and the corresponding type I receptor Alk3/6 functions are both essential for specification of the dorsal region of the embryo. Third, using anti-phospho-Smad1/5/8 immunostaining, we show that, despite its ventral transcription, the BMP2/4 ligand triggers receptor mediated signaling exclusively on the dorsal side of the embryo, one of the most extreme cases of BMP translocation described so far. We further report that the pattern of pSmad1/5/8 is graded along the dorsal-ventral axis and that two BMP2/4 target genes are expressed in nested patterns centered on the region with highest levels of pSmad1/5/8, strongly suggesting that BMP2/4 is acting as a morphogen. We also describe the very unusual ventral co-expression of chordin and bmp2/4 downstream of Nodal and demonstrate that Chordin is largely responsible for the spatial restriction of BMP2/4 signaling to the dorsal side. Thus, unlike in most organisms, in the sea urchin, a single ventral signaling centre is responsible for induction of ventral and dorsal cell fates. Finally, we show that Chordin may not be required for long-range diffusion of BMP2/4, describe a striking dorsal-ventral asymmetry in the expression of Glypican 5, a heparin sulphated proteoglycan that regulates BMP mobility, and show that this asymmetry depends on BMP2/4 signaling. Our study provides new insights into the mechanisms by which positional information is established along the dorsal-ventral axis of the sea urchin embryo, and more generally on how a BMP morphogen gradient is established in a multicellular embryo. From an evolutionary point of view, it highlights that although the genes used for dorsal-ventral patterning are highly conserved in bilateria, there are considerable variations, even among deuterostomes, in the manner these genes are used to shape a BMP morphogen gradient. During early development of many organisms, patterning along the dorsal-ventral axis is regulated by the activities of two signaling centers located on the ventral and dorsal sides of the embryo. One of these centers produces growth factors of the BMP family that act as morphogens, whereas the other center secretes BMP antagonists such as Chordin that regulate the flow of BMPs along the dorsal-ventral axis. Expression from these two signaling centers results in roughly complementary distributions of BMP and BMP antagonist. We have analyzed BMP-mediated dorsal-ventral axis patterning in embryos of sea urchins, which are phylogenetically close to vertebrates and extensively rely on cell-cell interactions for their development. We found that in sea urchins, unlike in most organisms, the activity of a single signaling center located on the ventral side is responsible for generating both the ventral and the dorsal sides of the embryo. In addition, we discovered that the BMP2/4 gene is co-expressed with Chordin in this ventral center but that the BMP2/4 protein is translocated to the opposite side of the embryo where it activates the genetic program responsible for dorsal differentiation. Our study reveals an unusual example of signaling at a distance by a BMP growth factor. It also highlights that although the proteins used for dorsal-ventral patterning are evolutionarily conserved, there are considerable variations in the manner in which these proteins can be used in different species to generate a gradient of BMP morphogen.
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