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Extracellular matrix stiffness and cell contractility control RNA localization to promote cell migration.

ABSTRACT: Numerous RNAs are enriched within cellular protrusions, but the underlying mechanisms are largely unknown. We had shown that the APC (adenomatous polyposis coli) protein controls localization of some RNAs at protrusions. Here, using protrusion-isolation schemes and RNA-Seq, we find that RNAs localized in protrusions of migrating fibroblasts can be distinguished in two groups, which are differentially enriched in distinct types of protrusions, and are additionally differentially dependent on APC. APC-dependent RNAs become enriched in high-contractility protrusions and, accordingly, their localization is promoted by increasing stiffness of the extracellular matrix. Dissecting the underlying mechanism, we show that actomyosin contractility activates a RhoA-mDia1 signaling pathway that leads to formation of a detyrosinated-microtubule network, which in turn is required for localization of APC-dependent RNAs. Importantly, a competition-based approach to specifically mislocalize APC-dependent RNAs suggests that localization of the APC-dependent RNA subgroup is functionally important for cell migration.Adenomatous polyposis coli (APC) regulates the localization of some mRNAs at cellular protrusions but the underlying mechanisms and functional roles are not known. Here the authors show that APC-dependent RNAs are enriched in contractile protrusions, via detyrosinated microtubules, and enhance cell migration.

SUBMITTER: Wang T

PROVIDER: S-EPMC5638855 | biostudies-other | 2017 Oct

REPOSITORIES: biostudies-other

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Extracellular matrix stiffness and cell contractility control RNA localization to promote cell migration.

Wang Tianhong T Hamilla Susan S Cam Maggie M Aranda-Espinoza Helim H Mili Stavroula S

Nature communications 20171012 1

Numerous RNAs are enriched within cellular protrusions, but the underlying mechanisms are largely unknown. We had shown that the APC (adenomatous polyposis coli) protein controls localization of some RNAs at protrusions. Here, using protrusion-isolation schemes and RNA-Seq, we find that RNAs localized in protrusions of migrating fibroblasts can be distinguished in two groups, which are differentially enriched in distinct types of protrusions, and are additionally differentially dependent on APC. ...[more]

PMID: 29026081

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Project description:The transient period of regeneration potential in the postnatal heart suggests molecular changes with maturation influence the cardiac response to damage. We have previously demonstrated that injury and exercise can stimulate cardiomyocyte proliferation in the adult heart suggesting a sensitivity to exogenous signals. Here, we consider whether exogenous fetal ECM and mechanically unloading interstitial matrix can drive regeneration after myocardial infarction (MI) surgery in low-regenerative hearts of day5 mice. Compared to controls, exogenous fetal ECM increases cardiac function and lowers fibrosis at 3 weeks post-injury and this effect can be augmented by softening heart tissue. In vitro experiments support a mechano-sensitivity to exogenous ECM signaling. We tested potential mechanisms and observed that fetal ECM increases nuclear YAP localization which could be enhanced by pharmacological stabilization of the cytoskeleton. Blocking YAP expression lowered fetal ECM effects though not completely. Lastly we observed mechanically unloading heart interstitial matrix increased agrin expression, an extracellular node in the YAP signaling pathway. Collectively, these data support a combined effect of exogenous factors and mechanical activity in altering agrin expression, cytoskeletal remodeling, and YAP signaling in driving cardiomyocyte cell cycle activity and regeneration in postnatal non-regenerative mice. STATEMENT OF SIGNIFICANCE: With the purpose of developing regenerative strategies, we investigate the influence of the local niche on the cardiac injury response. We conclude tissue stiffness, as anticipated in aging or disease, impairs regenerative therapeutics. Most novel, mechanical unloading facilitates enhanced cardiac regeneration only after cells are pushed into a permissive state by fetal biomolecules. Specifically, mechanical unloading appears to increase extracellular agrin expression that amplifies fetal-stimulation of nuclear YAP signaling which correlates with observed increases of cell cycle activity in cardiomyocytes. The results further suggest the cytoskeleton is critical to this interaction between mechanical unloading and independently actived YAP signaling. Using animal models, tissue explants, and cells, this work indicates that local mechanical stimuli can augment proliferating-permissive cardiomyocytes in the natural cardiac niche.

Dataset Information

Extracellular matrix stiffness and cell contractility control RNA localization to promote cell migration.

Publications

Extracellular matrix stiffness and cell contractility control RNA localization to promote cell migration.

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