MACF1 links Rapsyn to microtubule- and actin-binding proteins to maintain neuromuscular synapses

Oury, J.-F.; Liu, Yun; Töpf, Ana; Todorović, S.; Hoedt, Esthelle; Preethish‐Kumar, Veeramani; Neubert, Thomas A.; Lin, Weichun; Lochmüller, Hanns; Burden, Steven J.

doi:10.1083/jcb.201810023

Cited by 43 publications

(58 citation statements)

References 86 publications

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“…Previous studies have shown important roles of Macf1 in brain, muscle and lung development, and that Macf1 is crucial in maintaining normal tissue structure and functions of muscle and neural . In this study, we showed that deletion of Macf1 in osteoblasts delayed bone ossification of newborn mice and decreased the bone mass of adult mice.…”

Section: Discussionsupporting

confidence: 56%

“…In the present study, we constructed an osteoblast-specific Osterix Previous studies have shown important roles of Macf1 in brain, muscle and lung development, and that Macf1 is crucial in maintaining normal tissue structure and functions of muscle and neural. 12,13,31,32,34 In this study, we showed that deletion of Macf1 in osteoblasts delayed bone ossification of newborn mice and decreased the bone mass of adult mice. Furthermore, we found that Macf1 f/f Osx-Cre without rhBMP2 treatment that osteoblasts and adipocytes in bone marrow share a common progenitor, and the dynamic balance between them can influence the density and function of bone.…”

Section: Discussionmentioning

confidence: 62%

“…Macf1 can crosslink with actin and microtubules and plays pivotal roles in cytoskeletal dynamics, cell migration, neuronal growth and cell signal transduction . Studies have demonstrated that Macf1 has physiological functions in mammalian skin, nervous system, heart, retina, intestine and skeletal muscle . However, the function of Macf1 in bone tissue remains unclear.…”

Section: Introductionmentioning

confidence: 99%

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Deficiency of Macf1 in osterix expressing cells decreases bone formation by Bmp2/Smad/Runx2 pathway

Qiu

Lin

Zhao

et al. 2019

J Cellular Molecular Medi

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Microtubule actin cross‐linking factor 1 (Macf1) is a spectraplakin family member known to regulate cytoskeletal dynamics, cell migration, neuronal growth and cell signal transduction. We previously demonstrated that knockdown of Macf1 inhibited the differentiation of MC3T3‐E1 cell line. However, whether Macf1 could regulate bone formation in vivo is unclear. To study the function and mechanism of Macf1 in bone formation and osteogenic differentiation, we established osteoblast‐specific Osterix (Osx) promoter‐driven Macf1 conditional knockout mice (Macf1f/fOsx‐Cre). The Macf1f/fOsx‐Cre mice displayed delayed ossification and decreased bone mass. Morphological and mechanical studies showed deteriorated trabecular microarchitecture and impaired biomechanical strength of femur in Macf1f/fOsx‐Cre mice. In addition, the differentiation of primary osteoblasts isolated from calvaria was inhibited in Macf1f/fOsx‐Cre mice. Deficiency of Macf1 in primary osteoblasts inhibited the expression of osteogenic marker genes (Col1, Runx2 and Alp) and the number of mineralized nodules. Furthermore, deficiency of Macf1 attenuated Bmp2/Smad/Runx2 signalling in primary osteoblasts of Macf1f/fOsx‐Cre mice. Together, these results indicated that Macf1 plays a significant role in bone formation and osteoblast differentiation by regulating Bmp2/Smad/Runx2 pathway, suggesting that Macf1 might be a therapeutic target for bone disease.

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Section: Discussionsupporting

confidence: 56%

Section: Discussionmentioning

confidence: 62%

Section: Introductionmentioning

confidence: 99%

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Deficiency of Macf1 in osterix expressing cells decreases bone formation by Bmp2/Smad/Runx2 pathway

Qiu

Lin

Zhao

et al. 2019

J Cellular Molecular Medi

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“…7 A). Interestingly, MACF1 (microtubule-actin crosslinking factor) has been recently identified to bind to AChRs in a rapsyn-dependent manner (Oury et al, 2019). MACF1 is a microtubule plus end-binding protein shown to promote persistent microtubule growth and to connect the actin and microtubule cytoskeletal network (Leung et al, 1999).…”

Section: The Role Of Rapsyn and Nup88 In Ciliogenesismentioning

confidence: 99%

“…Signaling downstream of MuSK is only poorly understood, but it involves interactions of both MuSK and rapsyn to all three cytoskeleton networks, i.e. microtubules, the actin cytoskeleton and intermediate filaments (Aittaleb et al, 2015;Antolik et al, 2007;Bartoli et al, 2001;Dobbins et al, 2008;Ghasemizadeh et al, 2019;Li et al, 2016;Luiskandl et al, 2013;Mihailovska et al, 2014;Moransard et al, 2003;Oury et al, 2019). Rapsyn has, moreover, been found in non-muscle cell types Musil et al, 1989) and plays a role in lysosome clustering (Aittaleb et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Centrosome and ciliary abnormalities in fetal akinesia deformation sequence human fibroblasts

Jühlen

Martinelli

Vinci

et al. 2019

Preprint

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Ciliopathies are clinical disorders of the primary cilium with widely recognized phenotypic and genetic heterogeneity. Here we found that impaired ciliogenesis in fibroblasts derived from individuals with fetal akinesia deformation sequence (FADS).FADS refers to a broad spectrum of neuromuscular disorders arising from impaired fetal movement. We show that cells derived from two FADS individuals, one with an unknown genetic cause and one with bi-allelic pathogenic variants in RAPSN, have shorter and less primary cilia (PC), in association with alterations in posttranslational modifications in α -tubulin. Similarly, siRNA-mediated depletion of two known FADS proteins, the scaffold protein rapsyn and the nucleoporin NUP88, resulted in defective PC formation. Consistent with a role in ciliogenesis, rapsyn and NUP88 localized to centrosomes and PC. By proximity-ligation assays, we show that rapsyn and NUP88 are interacting and that both proteins are connecting to all three tubulin isoforms (α, ß, and γ ). The rapsyn-NUP88 interface, as well as their contact to microtubules, is perturbed in the examined FADS cells, similarly to their contact to microtubules. We suggest that the perturbed rapsyn-NUP88-tubulin interface leads to defects in PC formation and that defective ciliogenesis contributes to the pleiotropic defects seen in FADS.

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Slow‐channel myasthenia due to novel mutation in M2 domain of AChR delta subunit

Shen

Milone

Wang

et al. 2019

Ann Clin Transl Neurol

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ObjectiveTo characterize the molecular and phenotypic basis of a severe slow‐channel congenital myasthenic syndrome (SCCMS).MethodsIntracellular and single‐channel recordings from patient endplates; alpha‐bungarotoxin binding studies; direct sequencing of AChR genes; microsatellite analysis; kinetic analysis of AChR activation; homology modeling of adult human AChR structure.ResultsAmong 24 variants reported to cause SCCMS only two appear in the AChR δ‐subunit. We here report a 16‐year‐old patient harboring a novel δL273F mutation (δL294F in HGVS nomenclature) in the second transmembrane domain (M2) of the AChR δ subunit. Kinetic analyses with ACh and the weak agonist choline indicate that δL273F prolongs the channel opening bursts 9.4‐fold due to a 75‐fold increase in channel gating efficiency, whereas a previously identified εL269F mutation (εL289F in HGVS nomenclature) at an equivalent location in the AChR ε‐subunit prolongs channel opening bursts 4.4‐fold due to a 30‐fold increase in gating efficiency. Structural modeling of AChR predicts that inter‐helical hydrophobic interactions between the mutant residue in the δ and ε subunit and nearby M2 domain residues in neighboring α subunits contribute to structural stability of the open relative to the closed channel states.InterpretationThe greater increase in gating efficiency by δL273F than by εL269F explains why δL273F has more severe clinical effects. Both δL273F and εL269F impair channel gating by disrupting hydrophobic interactions with neighboring α‐subunits. Differences in the extent of impairment of channel gating in δ and ε mutant receptors suggest unequal contributions of ε/α and δ/α subunit pairs to gating efficiency.

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MACF1 links Rapsyn to microtubule- and actin-binding proteins to maintain neuromuscular synapses

Cited by 43 publications

References 86 publications

Deficiency of Macf1 in osterix expressing cells decreases bone formation by Bmp2/Smad/Runx2 pathway

Deficiency of Macf1 in osterix expressing cells decreases bone formation by Bmp2/Smad/Runx2 pathway

Centrosome and ciliary abnormalities in fetal akinesia deformation sequence human fibroblasts

Slow‐channel myasthenia due to novel mutation in M2 domain of AChR delta subunit

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