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Title: Opposing Nodal and BMP Signals Regulate Left–Right Asymmetry in the Sea Urchin Larva}
Article:
Abstract:
Nodal and BMP signals are important for establishing left-right( LR) asymmetry in vertebrates. In sea urchins, Nodal signaling prevents the formation of the rudiment on the right side. However, the opposing pathway to Nodal signaling during LR axis establishment is not clear. Here, we revealed that BMP signaling is activated in the left coelomic pouch, specifically in the veg2 lineage, but not in the small micromeres. By perturbing BMP activities, we demonstrated that BMP signaling is required for activating the expression of the left-sided genes and the formation of the left-sided structures. On the other hand, Nodal signals on the right side inhibit BMP signaling and control LR asymmetric separation and apoptosis of the small micromeres. Our findings show that BMP signaling is the positive signal for left-sided development in sea urchins, suggesting that the opposing roles of Nodal and BMP signals in establishing LR asymmetry are conserved in deuterostomes.
Introduction:
One of the most fascinating features of bilaterian development is the consistent left-right( LR) asymmetry of their internal organs. In the past two decades, studies of molecular pathways controlling LR asymmetry have broadened our knowledge regarding the dissimilar and conserved mechanisms among different animal models[1]. It has been suggested that the mechanisms of initial symmetry breaking are not conserved across different vertebrate classes[2]. For example, a leftward fluid flow generated by the posteriorly tilted nodal cilia initiates left-sided gene expression in the mouse embryo[3]. On the other hand, differential activities of ion pumps in early stage embryos are important for establishing LR asymmetry in the chick, frog, and zebrafish[4]. Although detailed symmetry-breaking mechanisms vary among different vertebrate species, the common outcome is the expression of nodal, which encodes a transforming growth factor β( TGFβ) ligand, in the left lateral plate mesoderm( LPM)[5]. The Nodal pathway not only regulates LR asymmetry in vertebrates but also controls the formation of the left-sided adult rudiment in sea urchins[6] and body chirality in snails[7]. Bone morphogenic protein( BMP), another TGFβ family member, is also involved in LR patterning[8]. In opposition to conserved nodal expression on the left side, BMP transcripts or activities are observed on the right side of the node or LPM. For example, bmp4 is expressed on the right side of Hensen's node in the chick embryo and initiates a right-sided signaling cascade[9]. Although bmp genes are expressed symmetrically in the LPM of the mouse and chick embryos, BMP activity is greater on the right side due to the presence of BMP antagonists on the left side[10]–[13]. A BMP/ALK2/Smad-mediated signaling pathway is also proposed to be active on the right side of the Xenopus embryo[14]. Therefore, right-sided BMP opposing left-sided Nodal seems to be a conserved feature. The role of BMP in LR patterning is largely unknown in invertebrates, even though right-sided expressed dpp-bmp2/4 plays important roles in shell formation and coiling in gastropods[15],[16]. Sea urchins belong to the phylum Echinodermata, which is characterized by a pentaradiate adult body plan. In indirect developing sea urchins, the adults are derived from bilaterally symmetric larvae. The transition from a bilaterally symmetric to pentasymmetric body plan relies on a LR asymmetrical control that results in the formation of an adult rudiment on the left side of the larva( Figure S1). During gastrulation, a coelomic pouch( CP) composed of veg2 mesoderm and small micromeres( Smm) forms at the archenteron tip and later separates into left and right pouches in the bilateral gastrula[17]. The first morphological signature of LR asymmetry in the pluteus larva is the extension of a duct-like structure, the hydroporic canal( HC), from the left CP to the aboral ectoderm where the hydropore forms[18]. The ciliated HC is thought to be an excretory organ that contributes to normal body width maintenance in the larva[19],[20] and later differentiates into a portion of the adult water vascular system[21]. The differentiated left coelom together with the invaginated left oral ectoderm, called the primary vestibule, develop into an adult rudiment with pentaradial symmetry[22],[23]. Our knowledge of the molecular mechanisms concerning LR patterning in sea urchins is relatively limited. It has been shown that sea urchin LR axis specification depends on cell interactions[24]. A series of microsurgery experiments revealed that the positioning of the adult rudiment on the left side is directed by signals from the right side[25]. Duboc et al. further demonstrated that nodal expression on the right side, which is reversed when compared to vertebrates, prevents the formation of the adult rudiment[6]. In addition, signals emitted from the micromeres also regulate LR asymmetry[26], although the identity of the micromere-derived signal remains unknown. It is also not known whether positive signals or a default pathway are required for the left-sided structure development. In this study, we focused on the role of the BMP pathway and examined the molecular basis of LR asymmetry in the sea urchin embryo. We found that bmp genes are symmetrically expressed in skeletogenic micromeres, but BMP signaling is asymmetrically activated in the left CP-derived HC. Through cell lineage analysis, we detected active BMP signaling in veg2 descendants but not in the Smm. We further provided evidence that BMP signaling is required for left-sided structure development and the expression of several left-sided marker genes. We also demonstrate that right-sided Nodal signaling restricts BMP activity and is involved in the asymmetrical separation and apoptosis of the Smm. We discuss these findings in the context of Nodal and BMP signaling in patterning LR asymmetry in the sea urchin embryo.
Discussion:
We demonstrated that elevating either Nodal or BMP signaling resulted in the loss of the other signal. This mutual antagonism between Nodal and BMP signaling has been observed during LR patterning in vertebrates. Nodal signaling inhibits BMP signals in the left LPM of mouse embryos by activating the expression of chordin and noggin genes, which encode BMP antagonists[10]. BMP signaling also has been shown to block Nodal signals in the right LPM of mouse, chick, and zebrafish embryos by activating the expression of lefty genes that encode Nodal antagonists[8],[55]. The inhibition of BMP signals by Nodal signaling has also been observed in sea urchin embryos during DV( aboral-oral) axis establishment. Nodal signaling in the oral ectoderm is required for the expression of chordin, which restricts BMP signals in the aboral ectoderm[31]. However, we could not detect any asymmetrical LR expression of genes encoding BMP antagonists, such as chordin, noggin, follistatin, dan, or gremlin in the sea urchin embryo( unpublished data). The second molecular mechanism to explain the mutual antagonism between Nodal and BMP signaling is the direct competition between the two signals for the limited amount of the common effector Smad4. In the mouse embryo, BMP signaling has been shown to set a repressive threshold for Nodal signaling in the LPM by limiting Smad4 availability[56]. The repressive role of Nodal signaling on BMP in the sea urchin embryo is evident given that increasing or blocking Nodal signaling results in the loss of or bilateral pSmad staining in CPs, respectively. However, the effects of BMP signaling on Nodal are complicated because increasing and blocking BMP signaling both result in the loss of nodal expression. These results suggest that BMP signaling is required for right-sided nodal expression in the sea urchin embryo. This positive role of BMP signaling on nodal gene expression has also been observed in vertebrates. In the absence of mouse embryonic BMP4, nodal expression is lost in the left LPM[57]. In chick embryos, implanting either bmp2-expressing cells[58] or BMP-soaked beads[59] in the LPM increases nodal expression. During the late segmentation stages of zebrafish embryos, BMP4 signaling is required to activate the expression of the nodal-related gene cyclops in the left LPM[60]. Therefore, BMP signaling can be a positive or negative regulator of Nodal signaling depending on the developmental stages and tissue layers during LR patterning in vertebrates. Although we observed LR asymmetrical BMP signaling with pSmad staining in the CPs in the sea urchin, bmp genes are transcribed in the skeletogenic mesenchyme cells near the aboral apex of the larva. These observations suggest that BMP ligands are secreted from these micromere-derived skeletogenic cells to control LR asymmetry. It was previously shown that when the micromere lineage was removed from embryos of sea urchin Hemicentrotus pulcherrimus, the LR placement of the rudiment was randomized[26]. BMP could be the micromere-derived signal that regulates larval LR polarity, although other signaling molecules may also be involved in this process. In sea urchin embryos, Smm form during the fifth cleavage and are regulated by a set of conserved germline lineage genes, including vasa, nanos2, and seawi[37]. Adults from Smm-deleted embryos formed small gonads without gametes[61]. Therefore, Smm are required for germline specification in sea urchins. Smm lineage fate is maintained by Nanos[52], which is also required for Smm descendant survival[51]. Studies in fly and vertebrates have also shown that Nanos has a conserved role in maintaining germline identity by preventing apoptosis[62]–[64]. In this study, we showed that Nodal signaling acts on the Smm partitioned in the right CP. Nodal signaling perturbation affected both nanos2 expression and cell death. These results suggest that Nodal signaling in the right CP represses nanos2 expression in the Smm, which leads to cell death. To our knowledge, the role of Nodal signaling in repressing the expression of germline lineage genes such as nanos has not been reported in other systems. Intriguingly, Nodal is capable of inducing apoptosis in adult ovary during follicular degeneration and human trophoblast cells during normal placentation[65],[66]. Therefore, there may be a conserved role for Nodal to induce apoptosis in extraembryonic tissues. In the case of sea urchins, Nodal signaling-induced apoptosis in the right Smm is essential for normal development, and a lack of Nodal results in bilateral rudiments that give rise to a juvenile composed of two conjoined urchins[6].
Bilateral animals that are externally symmetric in appearance often have internal organs that are asymmetric with respect to the left and right sides of their bodies . Two signals , Nodal and BMP , have been shown to establish this asymmetry during vertebrate embryogenesis . We investigate here whether the same mechanisms that establish left-right patterning in vertebrates are conserved in invertebrate animals , specifically in the California purple sea urchin . This sea urchin passes through various stages in its lifecycle before developing to adulthood , including a feeding larva stage in which the tissue that goes on to form the adult , the so-called adult rudiment , forms on the left side . Previous studies have shown that right-sided Nodal signaling in sea urchins prevents the formation of the adult rudiment . In this study , we show that BMP signaling is activated on the left side and is required for the development of this left-sided structure . We also demonstrate that Nodal signaling blocks BMP activity and induces apoptosis of the tissue that forms the adult rudiment on the right side . We propose that the roles of Nodal and BMP signals in establishing left-right asymmetry are evolutionarily conserved .