MMP21 behaves as a fluid flow transported morphogen to impart laterality during development
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eLife Assessment
This report explores the role of matrix metalloprotease MMP21 in left-right patterning in Xenopus. Based on a series of compelling experiments, the authors demonstrate that MMP21 can be secreted and acts upstream of dand5 without affecting cilia flow. The experiments are interesting and valuable; however, the claims by the authors lack consideration of other models that could also explain their findings.
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Abstract
Heterotaxy (HTX) is frequently caused by deleterious variants in the gene encoding Matrix metallopeptidase 21 (MMP21). However, the underlying pathomechanism has not been ascertained. In this study, we report on a novel HTX-associated MMP21 knockout allele in humans and investigate the peptidase’s role during laterality development using Xenopus embryos as animal model. The targeted inactivation of mmp21 in f0 mutant Xenopus successfully phenocopied the human HTX condition, yet the cilia-driven leftward fluid flow, which initiates asymmetric gene activity at the left-right organizer (LRO), was unaltered in mmp21 null frogs. Instead, our analysis of downstream events revealed that flow response, the left-sided repression of dand5 , could not take place. Remarkably, gain-of-function experiments demonstrated that Mmp21 spreads over LRO cells and triggers flow response. Additionally, Mmp21 functions upstream of Cirop, another metallopeptidase, which we found specifically localized to LRO cilia. Thus, our findings suggest that Mmp21 may be the long-sought morphogen, which is actively transported by the leftward fluid flow to Cirop-laden cilia, in order to specify the left side of the embryo.
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eLife Assessment
This report explores the role of matrix metalloprotease MMP21 in left-right patterning in Xenopus. Based on a series of compelling experiments, the authors demonstrate that MMP21 can be secreted and acts upstream of dand5 without affecting cilia flow. The experiments are interesting and valuable; however, the claims by the authors lack consideration of other models that could also explain their findings.
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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 …
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.
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