Neuroprotective role of Hippo signaling by microtubule stability control in C. elegans
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eLife Assessment
In their valuable study, Lee et al. explore a role for the Hippo signaling pathway, specifically wts-1/LATS and the downstream regulator yap, in age-dependent neurodegeneration and microtubule dynamics using C. elegans mechanosensory neurons as a model. The authors demonstrate that disruption of wts-1/LATS leads to age-associated morphological and functional neuronal abnormalities, linked to enhanced microtubule stabilization, and shows a genetic connection between yap and microtubule stability. Despite some mechanistic gaps, the study employs robust genetic and molecular approaches to reveal a convincing link between the Hippo pathway, microtubule dynamics, and neurodegeneration.
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Abstract
The evolutionarily conserved Hippo (Hpo) pathway has been shown to impact early development and tumorigenesis by governing cell proliferation and apoptosis. However, its post-developmental roles are relatively unexplored. Here, we demonstrate its roles in post-mitotic cells by showing that defective Hpo signaling accelerates age-associated structural and functional decline of neurons in C. elegans . Loss of wts-1 /LATS resulted in premature deformation of touch neurons and impaired touch responses in a yap-1/ YAP-dependent manner. Decreased movement as well as microtubule destabilization by treatment with colchicine or disruption of microtubule stabilizing genes alleviated the neuronal deformation of wts-1 mutants. Colchicine exerted neuroprotective effects even during normal aging. In addition, the deficiency of a microtubule-severing enzyme spas-1 also led to precocious structural deformation. These results consistently suggest that hyper-stabilized microtubules in both wts-1 -deficient neurons and normally aged neurons are detrimental to the maintenance of neuronal structural integrity. In summary, Hpo pathway governs the structural and functional maintenance of differentiated neurons by modulating microtubule stability, raising the possibility that the microtubule stability of fully developed neurons could be a promising target to delay neuronal aging. Our study provides potential therapeutic approaches to combat age- or disease-related neurodegeneration.
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eLife Assessment
In their valuable study, Lee et al. explore a role for the Hippo signaling pathway, specifically wts-1/LATS and the downstream regulator yap, in age-dependent neurodegeneration and microtubule dynamics using C. elegans mechanosensory neurons as a model. The authors demonstrate that disruption of wts-1/LATS leads to age-associated morphological and functional neuronal abnormalities, linked to enhanced microtubule stabilization, and shows a genetic connection between yap and microtubule stability. Despite some mechanistic gaps, the study employs robust genetic and molecular approaches to reveal a convincing link between the Hippo pathway, microtubule dynamics, and neurodegeneration.
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Reviewer #1 (Public review):
Summary:
In this manuscript, the authors investigate the role of microtubule dynamics and its effects on neuronal aging. Using C. elegans as a model, the authors investigate the role of evolutionarily conserved Hippo pathway in microtubule dynamics of touch receptor neurons (TRNs) in an age-dependent manner. Using genetic, molecular, behavioral, and pharmacological approaches, the authors show that age-dependent loss of microtubule dynamics might underlie structural and functional aging of TRNs. Further, the authors show that the Hippo pathway specifically functions in these neurons to regulate microtubule dynamics. Specifically, authors show that hyperactivation of YAP-1, a downstream component of the Hippo pathway that is usually inhibited by the kinase activity of the upstream components of the pathway, …
Reviewer #1 (Public review):
Summary:
In this manuscript, the authors investigate the role of microtubule dynamics and its effects on neuronal aging. Using C. elegans as a model, the authors investigate the role of evolutionarily conserved Hippo pathway in microtubule dynamics of touch receptor neurons (TRNs) in an age-dependent manner. Using genetic, molecular, behavioral, and pharmacological approaches, the authors show that age-dependent loss of microtubule dynamics might underlie structural and functional aging of TRNs. Further, the authors show that the Hippo pathway specifically functions in these neurons to regulate microtubule dynamics. Specifically, authors show that hyperactivation of YAP-1, a downstream component of the Hippo pathway that is usually inhibited by the kinase activity of the upstream components of the pathway, results in microtubule stabilization and that might underlie the structural and functional decline of TRNs with age. However, how the Hippo pathway regulates microtubule dynamics and neuronal aging was not investigated by the authors.
Strengths:
This is a well-conducted and well-controlled study, and the authors have used multiple approaches to address different questions.
Weaknesses:
There are no major weaknesses identified, except that the effect of the Hippo pathway seems to be specific to only a subset of neurons. I would like the authors to address the specificity of the effect of the Hippo pathway in TRNs, in their resubmission.
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Reviewer #2 (Public review):
Summary:
This study examines a novel role of the Hpo signaling pathway, specifically of wts-1/LATS and the downstream regulator of gene expression, yap, in age-related neurodegeneration in C. elegans touch-responsive mechanosensory neurons, ALM and PLM. The study shows that knockdown or deletion of wts-1/LATS causes age-associated morphological abnormalities of these neurons, accompanied by functional loss of touch responsiveness. This is further associated with enhanced, abnormal, microtubule stabilization in these neurons.
Strengths:
This study examines a novel role of the Hpo signaling pathway, specifically of wts-1/LATS and the downstream regulator of gene expression, yap, in age-related neurodegeneration in C. elegans touch-responsive mechanosensory neurons, ALM and PLM. The study shows that knockdown …
Reviewer #2 (Public review):
Summary:
This study examines a novel role of the Hpo signaling pathway, specifically of wts-1/LATS and the downstream regulator of gene expression, yap, in age-related neurodegeneration in C. elegans touch-responsive mechanosensory neurons, ALM and PLM. The study shows that knockdown or deletion of wts-1/LATS causes age-associated morphological abnormalities of these neurons, accompanied by functional loss of touch responsiveness. This is further associated with enhanced, abnormal, microtubule stabilization in these neurons.
Strengths:
This study examines a novel role of the Hpo signaling pathway, specifically of wts-1/LATS and the downstream regulator of gene expression, yap, in age-related neurodegeneration in C. elegans touch-responsive mechanosensory neurons, ALM and PLM. The study shows that knockdown or deletion of wts-1/LATS causes age-associated morphological abnormalities of these neurons, accompanied by functional loss of touch responsiveness. This is further associated with enhanced, abnormal, microtubule stabilization in these neurons. Strong pharmacological and especially genetic manipulations of MT-stabilizing or severing proteins show a strong genetic link between yap and regulation of MTs stability. The study is strong and uses robust approaches, especially strong genetics. The demonstrations on the aging-related roles of the Hpo signaling pathway, and the link to MTs, are novel and compelling. Nevertheless, the study also has mechanistic weaknesses (see below).
Weaknesses:
Specific comments:
(1) The study demonstrates age-specific roles of the Hpo pathway, specifically of wts-1/LATS and yap, specifically in TRN mechanosensory neurons, without observing developmental defects in these neurons, or effects in other neurons. This is a strong demonstration. Nevertheless, the study does not address whether there is a correlation of Hpo signaling pathway activity decline specifically in these neurons, and not other neurons, and at the observed L4 stage and onwards (including the first day of adulthood, 1DA stage). Such demonstrations of spatio-temporal regulation of the Hpo signaling pathway and its activation seem important for linking the Hpo pathway with the observed age-related neurodegeneration. Can this age-related response be correlated to indeed a decline in Hpo signaling during adulthood? Especially at L4 and onwards? It will be informative to measure this by examining the decline in wts1 as well as yap levels and yap nuclear localization.
(2) The Hpo pathway eventually activates gene expression via yap. Although the study uses robust genetic manipulations of yap and wts-1/LATS, it is not clear whether the observed effects are attributed to yap-mediated regulation of gene expression (see 3).
(3) The observations on the abnormal MT stabilization, and the subsequent genetic examinations of MT-stability/severing genes, are a significant strength of the study. Nevertheless, despite the strong genetic links to yap and wts-1/LATS, it is not clear whether MT-regulatory genes are regulated by transcription downstream of the Hpo pathway, thus not enabling a strong causal link between MT regulation and Hpo-mediated gene expression, making this strong part of the study mechanistically circumstantial. Specifically, it will be good to examine whether the genes addressed herein, for example, Spastin, are transcriptionally regulated downstream of the Hpo pathway. This comment is augmented by the finding that in the wts-1/ yap-1 double mutants, MT abnormality, and subsequent neuronal morphology and touch responses are restored, clearly indicating that there is an associated transcriptional regulation
Other comments:
(1) The TRN-specific knockdown of wts-1 and yap-1 is a clear strength. Nevertheless, these do not necessarily show cell-autonomous effects, as the yap transcription factor may regulate the expression of external cues, secreted or otherwise, thus generating non-cell autonomous effects. For example, it is known that yap regulates TGF-beat expression and signaling.
(2) Continuing from comment (3) above, it seems that many of the MT-regulators chosen here for genetic examinations were chosen based on demonstrated roles in neurodegeneration in other studies. It would be good to show whether these MT-associated genes are directly regulated by transcription by the Hpo pathway.
(3) The impairment of the touch response may not be robust: it is only a 30-40% reduction at L4, and even less reduction at 1DA. It would be good to offer possible explanations for this finding.
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