Shuttling establishes the secondary body axis in the starlet sea anemone

Summary by Selvaraj Velanganni: Mörsdorf, D., Prünster, MM., Genikhovich, G., 2024. Chordin-mediated BMP shuttling patterns the secondary body axis in a cnidarian. bioRxiv 2024.05.27.596067

Image credit: Midjourney

BMP signaling is crucial for establishing the secondary body axis in the bilaterian phylum and is also conserved in bilaterally symmetric Cnidarians such as the starlet sea anemone Nematostella vectensis. The BMP signaling pathway involves the secreted ligands BMP 2/4 and BMP 5-8, which bind to a receptor complex, enabling the phosphorylation of the signaling effector SMAD1/5, which results in transcriptional regulation of key genes including the extracellular BMP inhibitor Chordin in Nematostella. Chordin is a double-edged sword: it exhibits anti-BMP effects by binding to the BMP ligand which blocks BMP interaction with its receptor, but also has pro-BMP effects, promoting long-range activation of BMP in various animals like Drosophila and Xenopus [1-3].

The phylogenetic conservation of the pathway ligands and their inhibitor Chordin suggests that the molecules required for the formation of the BMP-dependent body axis either (1) evolved prior to divergence of Cnidaria and Bilateria or (2) evolved convergently among these phyla. To understand this, Mörsdorf et al. evaluated the “mode of action” of BMP ligand dispersal and Chordin’s role in the mechanism of establishing a secondary body axis in the bilaterally symmetric sea anemone [4].  

First, by injecting a mixture of BMP2/4 and BMP5-8 mRNA, the authors showed that these ligands likely form biologically relevant heterodimers necessary in Nematostella secondary axis formation, which is consistent with observations in different developmental contexts in Bilateria. Next, they examined the current model of BMP dispersal, which suggests that BMP ligands diffuse through the extracellular layer between outer ectodermal layer and inner mesodermal and endodermal layer (mesoglea). To test this, the authors created a fusion protein by attaching a fluorescent protein, sfGFP, to BMP2/4 ligands. This showed that (1) BMP ligands are secreted towards the apical or apical lateral surface of the ectodermal cells, and (2) mature ligands are retained on the cell surface without detection of free extracellular ligands, suggesting possible interactions between ligands and extracellular matrix components or receptors. Notably, these observations are consistent with observations made in Drosophila.

In other bilaterian models, the loss of Chordin results in the extension of the pSMAD1/5 positive domain, indicating an expansion of BMP signaling activity [5]. However, in Nematostella, loss of Chordin results in the loss of BMP activity, suggesting that Chordin may have pro-BMP activity. To test Chordin’s role in pro-BMP activity, the authors performed localized ectopic expression experiments with wild-type Chordin and membrane tethered Chordin-CD2. The wild-type mobile Chordin enabled strong BMP activity, while the membrane tethered Chordin-CD2 was unable to activate BMP signaling on the opposite side of the Chordin expression, but it did activate BMP signaling in the Chordin-CD2 source, providing evidence for a role for mobile Chordin in pro-BMP activity.

In summary, the BMP ligands and Chordin present in the Cnidarian Nematostella and Bilateria have the potential to break symmetry and establish the secondary axis through Chordin mediated shuttling of BMP.  This is the first study showing the evidence of BMP shuttling in Cnidarians and suggests this mechanism may have been present in the ancestors of the Cnidarian-Bilaterian.

1. Little, S.C., Mullins, M.C., 2009. Bone morphogenetic protein heterodimers assemble heteromeric type I receptor complexes to pattern the dorsoventral axis. Nat Cell Biol 11, 637- 643.

2. Mizutani, C.M., Nie, Q., Wan, F.Y., Zhang, Y.T., Vilmos, P., Sousa-Neves, R., Bier, E., Marsh, J.L., Lander, A.D., 2005. Formation of the BMP activity gradient in the Drosophila embryo. Dev Cell 8, 915-924.

3. Mörsdorf, D., Knabl, P., Genikhovich, G., 2024. Highly conserved and extremely evolvable: BMP signalling in secondary axis patterning of Cnidaria and Bilateria. Dev Genes Evol.

4.  Mörsdorf, D., Prünster, MM., Genikhovich, G., 2024Chordin-mediated BMP shuttling patterns the secondary body axis in a cnidarian. bioRxiv 2024.05.27.596067; doi: https://doi.org/10.1101/2024.05.27.596067

5.  Pomreinke, A.P., Soh, G.H., Rogers, K.W., Bergmann, J.K., Bläßle, A.J., Müller, P., 2017. Dynamics of BMP signaling and distribution during zebrafish dorsal-ventral patterning. Elife 6.