Nestin contributes to skeletal muscle homeostasis and regeneration

Lindqvist, Julia; Torvaldson, Elin; Gullmets, Josef; Karvonen, Henok; Nagy, András; Taimen, Pekka; Eriksson, John E.

doi:10.1242/jcs.202226

Cited by 28 publications

(27 citation statements)

References 52 publications

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“…Interestingly, Nes −/− mice showed increased explorative activity when maintained in the IntelliCage housing, as assessed by the number of visits and nose pokes in the corners of the IntelliCages. This was not detected by previous investigations that did not reveal increased locomotor activity or anxiety of Nes −/− mice as assessed by the open field test [28] or voluntary treadmill running [38]. Thus, the automated dynamic Intellicage home cage system might be more sensitive for assessing some aspects of mouse behavior.…”

Section: Discussioncontrasting

confidence: 55%

Nestin Null Mice Show Improved Reversal Place Learning

et al. 2019

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The intermediate filament protein nestin is expressed by neural stem cells, but also by some astrocytes in the neurogenic niche of the hippocampus in the adult rodent brain. We recently reported that nestin-deficient (Nes −/−) mice showed increased adult hippocampal neurogenesis, reduced Notch signaling from Nes −/− astrocytes to the neural stem cells, and impaired long-term memory. Here we assessed learning and memory of Nes −/− mice in a home cage set up using the IntelliCage system, in which the mice learn in which cage corner a nose poke earns access to drinking water. Nes −/− and wildtype mice showed comparable place learning assessed as the incorrect corner visit ratio and the incorrect nose poke ratio. However, during reversal place learning, a more challenging task, Nes −/− mice, compared to wildtype mice, showed improved learning over time demonstrated by the incorrect visit ratio and improved memory extinction over time assessed as nose pokes per visit to the previous drinking corner. In addition, Nes −/− mice showed increased explorative activity as judged by the increased total numbers of corner visits and nose pokes. We conclude that Nes −/− mice exhibit improved reversal place learning and memory extinction, a finding which together with the previous results supports the concept of the dual role of hippocampal neurogenesis in cognitive functions.

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Section: Discussioncontrasting

confidence: 55%

Nestin Null Mice Show Improved Reversal Place Learning

et al. 2019

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“…Whereas mAKAP␤-dependent signaling explains how MEF2-HDAC complexes can be dissociated, the protein kinase(s) responsible for phosphorylating MEF2D Ser-444 in myocytes and maintaining HDAC binding is unknown. Onecandidateiscyclin-dependentprotein5(Cdk5),whichphosphorylates Ser-444 in neurons and heterologous cells (9,27) and is inhibited by nestin during skeletal myoblast differentiation (28). It is worth noting that whereas the class IIa HDACs HDAC4 and HDAC5 can both bind MEF2D, neither is a MEF2D deacetylase (29).…”

Section: Makap␤ Can and Mef2d Regulationmentioning

confidence: 99%

Muscle A-kinase–anchoring protein-β–bound calcineurin toggles active and repressive transcriptional complexes of myocyte enhancer factor 2D

Paris

Thakur

et al. 2019

Journal of Biological Chemistry

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Edited by Roger J. ColbranMyocyte enhancer factor 2 (MEF2) transcription factors are key regulators of the development and adult phenotype of diverse tissues, including skeletal and cardiac muscles. Controlled by multiple post-translational modifications, MEF2D is an effector for the Ca 2؉ /calmodulin-dependent protein phosphatase calcineurin (CaN, PP2B, and PPP3). CaN-catalyzed dephosphorylation promotes the desumoylation and acetylation of MEF2D, increasing its transcriptional activity. Both MEF2D and CaN bind the scaffold protein muscle A-kinaseanchoring protein ␤ (mAKAP␤), which is localized to the nuclear envelope, such that C2C12 skeletal myoblast differentiation and neonatal rat ventricular myocyte hypertrophy are inhibited by mAKAP␤ signalosome targeting. Using immunoprecipitation and DNA-binding assays, we now show that the formation of mAKAP␤ signalosomes is required for MEF2D dephosphorylation, desumoylation, and acetylation in C2C12 cells. Reduced MEF2D phosphorylation was coupled to a switch from type IIa histone deacetylase to p300 histone acetylase binding that correlated with increased MEF2D-dependent gene expression and ventricular myocyte hypertrophy. Together, these results highlight the importance of mAKAP␤ signalosomes for regulating MEF2D activity in striated muscle, affirming mAKAP␤ as a nodal regulator in the myocyte intracellular signaling network. 3 The abbreviations used are: by guest on July 9, 2020 http://www.jbc.org/ Downloaded from Figure 5. Regulation of MEF2D-HDAC5 binding. A, C2C12 cells co-transfected with expression plasmids for GFP-and FLAG-tagged MEF2D and GFP-tagged HDAC5 were cultured in GM or DM for 3 h before immunoprecipitation using FLAG antibodies and Western blotting using MEF2D and HDAC5 antibodies. p (one-way ANOVA) ϭ 0.003. B, HEK293 cells were transfected with GFP-and FLAG-tagged MEF2D mutants and GFP-HDAC5 before immunoprecipitation using FLAG antibodies and Western blotting as in A. p (one-way ANOVA) Ͻ 0.0001. C, same as A except using C2C12 cells transfected with mAKAP or control siRNA. p (two-way ANOVA for both factors and interaction) Ͻ 0.04. D, same as A except using C2C12 cells co-expressing mCherry or CBD-mCherry. p (two-way ANOVA for growth media and interaction) Ͻ 0.04. n ϭ 3 independent experiments for all panels. Downloaded fromFigure 7. Calcineurin-dependent regulation of MEF2D-p300 DNA complexes. A, C2C12 cells expressing GFP-and FLAG-tagged MEF2D were cultured in GM or DM in the absence or presence of cyclosporin A (500 nM) for 3 h before pulldown assay using a biotinylated oligonucleotide based upon a Myh7 MyoD cis-active element (24) and Western blotting using MEF2D antibodies. Myh7m is a mutant oligonucleotide control. p (one-way ANOVA) ϭ 0.004. B, same as in A except using HEK293 cells co-expressing mutant MEF2D proteins. p (two-way ANOVA for MEF2D mutants and interaction) Ͻ 0.04. C, same as A except C2C12 cells transfected with mAKAP or control siRNA. D, same as A except using C2C12 cells co-expressing mCherry or CBD-mCherry. p (two-way ANOVA f...

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“…Since then it has been widely described as a marker for stem or progenitor cells, mainly in the developing central nervous system 2 , 3 , but also heart 4 , 5 , bone marrow 6 , and others. Following cell differentiation, nestin is reportedly replaced by other cell-type specific IF 7 – 9 , and its expression is predominantly restricted to areas of regeneration in healthy adult tissues 3 , such as skeletal muscle 10 , hair follicles 11 , dopaminergic neurons 12 and neural stem cells 13 , 14 . Nestin is also expressed in kidney podocytes 15 , 16 and the neuromuscular junction 17 .…”

Section: Introductionmentioning

confidence: 99%

A systems-approach reveals human nestin is an endothelial-enriched, angiogenesis-independent intermediate filament protein

Dusart

Fagerberg

Perisic

et al. 2018

Sci Rep

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The intermediate filament protein nestin is expressed during embryonic development, but considered largely restricted to areas of regeneration in the adult. Here, we perform a body-wide transcriptome and protein-profiling analysis to reveal that nestin is constitutively, and highly-selectively, expressed in adult human endothelial cells (EC), independent of proliferative status. Correspondingly, we demonstrate that it is not a marker for tumour EC in multiple malignancy types. Imaging of EC from different vascular beds reveals nestin subcellular distribution is shear-modulated. siRNA inhibition of nestin increases EC proliferation, and nestin expression is reduced in atherosclerotic plaque neovessels. eQTL analysis reveals an association between SNPs linked to cardiovascular disease and reduced aortic EC nestin mRNA expression. Our study challenges the dogma that nestin is a marker of proliferation, and provides insight into its regulation and function in EC. Furthermore, our systems-based approach can be applied to investigate body-wide expression profiles of any candidate protein.

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Nestin contributes to skeletal muscle homeostasis and regeneration

Cited by 28 publications

References 52 publications

Nestin Null Mice Show Improved Reversal Place Learning

Nestin Null Mice Show Improved Reversal Place Learning

Muscle A-kinase–anchoring protein-β–bound calcineurin toggles active and repressive transcriptional complexes of myocyte enhancer factor 2D

A systems-approach reveals human nestin is an endothelial-enriched, angiogenesis-independent intermediate filament protein

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