Peer review process
Not revised: This Reviewed Preprint includes the authors’ original preprint (without revision), an eLife assessment, and public reviews.
Read more about eLife’s peer review process.Editors
- Reviewing EditorMustafa KhokhaYale University, New Haven, United States of America
- Senior EditorDidier StainierMax Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
Joint Public Review:
The manuscript describes the role of mmp21, a metallopeptidase, in left-right patterning. MMP21 has been implicated in genetic studies of patients with heterotaxy and the authors add an additional case. However, a molecular mechanism for Htx/LR patterning defects is not clear although one previous study implicated Notch signaling. The authors find that mmp21 does indeed cause LR patterning defects in Xenopus consistent with work in mice and zebrafish without affecting cilia motility. Importantly, the authors extend this work to place mmp21 in the LR pathway between dand5 (in the nodal cascade) and the cilia-driven sensation of flow. With RNA overexpression studies, the authors show MMP21 can induce Nodal signaling bilaterally suggesting it is an activator of the pathway, potentially through regulation of dand5 asymmetry. The authors also show that the role of MMP21 is upstream of another matrix metalloprotease CIROP which is tethered to the plasma membrane and possibly the cilium. They propose that mmp21, which is secreted, may represent a morphogen that is asymmetrically distributed along the LR axis due to cilia-driven flow and sensed by sensory cilia in the LRO.
The authors attempt to address a highly controversial subject in the LR patterning field, that is, the debate between Nodal Vesicular Particles (NVP, ie morphogens) being driven by cilia to activate signaling on the left and the Two Cilia model which posits that mechanosensation of fluid flow and not morphogens drive asymmetric organogenesis.
The model they propose is that mmp21 is secreted in the center of the LRO. LRO cilia generate leftward flow driving mmp21 to the left where sensory cilia at the LRO margin detect the mmp21 via cirop and suppress dand5, leading to activation of Nodal and Pitx2 expression.
First and foremost, the authors need to consider alternative models in the discussion and acknowledge the strengths and weaknesses of their work. All three reviewers felt that their conclusion that mmp21 is a morphogen is premature and that other models could also fit their data which needs to be discussed. The authors need to soften the conclusion that other models have been excluded.
