Spatiotemporal control of actomyosin contractility by MRCKβ signaling drives phagocytosis

Zihni, Ceniz; Georgiadis, Anastasios; Ramsden, Conor; Sánchez-Heras, Elena; Haas, Alexis J.; Nommiste, Britta; Semenyuk, Olha; Bainbridge, James W.; Coffey, PJ; Smith, Alexander J.; Ali, Robin R.; Balda, María S.; Matter, Karl

doi:10.1083/jcb.202012042

Cited by 12 publications

(6 citation statements)

References 66 publications

(111 reference statements)

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“…MRCK has recently emerged as a new player in actomyosin contractility in a variety of mammalian systems, including epithelial homeostasis, cell adhesion, and phagocytosis ( Ando et al, 2013 ; Marston et al, 2016 ; Gagliardi et al, 2018 ; Zihni et al, 2017 , 2022 ; Zihni, 2021 ). MRCK was also implicated in the regulation of cell motility and invasiveness and could provide a druggable target in several cancers ( Tan et al, 2008 ; Unbekandt and Olson, 2014 ; Unbekandt et al, 2018 ; Kurimchak et al, 2020 ; East and Asquith, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

MRCK activates mouse oocyte myosin II for spindle rotation and male pronucleus centration

Bourdais,

Dehapiot,

Halet

2023

Journal of Cell Biology

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Asymmetric meiotic divisions in oocytes rely on spindle positioning in close vicinity to the cortex. In metaphase II mouse oocytes, eccentric spindle positioning triggers cortical polarization, including the build-up of an actin cap surrounded by a ring of activated myosin II. While the role of the actin cap in promoting polar body formation is established, ring myosin II activation mechanisms and functions have remained elusive. Here, we show that ring myosin II activation requires myotonic dystrophy kinase-related Cdc42-binding kinase (MRCK), downstream of polarized Cdc42. MRCK inhibition resulted in spindle rotation defects during anaphase II, precluding polar body extrusion. Remarkably, disengagement of segregated chromatids from the anaphase spindle could rescue rotation. We further show that the MRCK/myosin II pathway is activated in the fertilization cone and is required for male pronucleus migration toward the center of the zygote. These findings provide novel insights into the mechanism of myosin II activation in oocytes and its role in orchestrating asymmetric division and pronucleus centration.

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Section: Discussionmentioning

confidence: 99%

MRCK activates mouse oocyte myosin II for spindle rotation and male pronucleus centration

Bourdais,

Dehapiot,

Halet

2023

Journal of Cell Biology

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“…By doing this comparison using retinas with and without β -actin, we detected several proteins that exhibit different interaction with the actin filaments in wildtype and Actb cg/cg retina (Figure 6), suggesting a differential interaction of these proteins with β - and γ -actin and pointing to possible molecular mechanisms of the observed phenotypes. First, through α v β 5 integrin on apical RPE membrane [45, 46, 47], talin and vinculin connect OS with RPE actin cytoskeleton [42], therefore the weak-ened binding of talin and vinculin with F-actin in the Actb cg/cg likely interferes with the “molecular clutch function” [48, 49] of this complex. Second, because ezrin promotes morphogenesis of apical microvilli of RPE [33], the increased interaction of ezrin with F-actin in the Actb cg/cg can lead to increased length of the microvilli.…”

Section: Discussionmentioning

confidence: 99%

“…Third, the overall increase (with longer microvilli) of the phosphorylated ERM (p-ERM shown in Figure 1D) in the Actb cg/cg can lead to decreased activation of non-muscle myosin II [50]. Decreased activation of non-muscle myosin II hampers the clustering of integrin, talin, vinculin, and F-actin at phagocytic cups [42] and causes significant phagocytic defects [35]. Thus in the Actb cg/cg retina, RPE microvilli have more freedom to extend further along OS and phagocytosis of OS tips by RPE is retarded (Figure 7).…”

Section: Discussionmentioning

confidence: 99%

“…We specifically tested 10 actin-binding proteins known to be important for RPE microvilli and OS phagocytosis: annexin A2 and A5 [31,32], ezrin [33,34], non-muscle myosin-IIa and -IIb [35,36], unconventional myosin-VI and -VIIa [37,38,39,40], talin and vinculin [41,42]. We were able to reliably quantify 9 of them from mass spectrometry data and found that all except one (myosin-IIa, encoded by Myh9) differentially bind to F-actin in wildtype and Actb cg/cg retina (Figure 6A).…”

Section: Replacing β-Actin With γ-Actin Significantly Changes the Int...mentioning

confidence: 99%

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β-actin is essential for structural integrity and physiological function of the retina

Vedula¹,

Fina²,

Bell³

et al. 2023

Preprint

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Lack of non-muscle β-actin gene (Actb) leads to early embryonic lethality in mice, however mice with β- to γ-actin replacement develop normally and show no detectable phenotypes at young age. Here we investigated the effect of this replacement in the retina. During aging, these mice have accelerated degeneration of retinal structure and function, including elongated microvilli and defective mitochondria of retinal pigment epithelium (RPE), abnormally bulging photoreceptor outer segments (OS) accompanied by reduced transducin concentration and light sensitivity, and accumulation of autofluorescent microglia cells in the subretinal space between RPE and OS. These defects are accompanied by changes in the F-actin binding of several key actin interacting partners, including ezrin, myosin, talin, and vinculin known to play central roles in modulating actin cytoskeleton and cell adhesion and mediating the phagocytosis of OS. Our data show that β-actin protein is essential for maintaining normal retinal structure and function.

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“…RCS rats carry a mutation in MERTK gene coding a receptor Mer tyrosine kinase (MerTK) [262]. MerTK is a widely expressed receptor involved in phagocytosis of shed POS by the RPE as well as apoptotic bodies by macrophages and microglia [262][263][264][265]. Mutations in human MERTK can cause early-onset retinal degenerations including rod-cone dystrophy (also known as retinitis pigmentosa) and cone-rod dystrophy [266].…”

Section: Sources Of Fluorescence In the Retinamentioning

confidence: 99%

Lipofuscin, Its Origin, Properties, and Contribution to Retinal Fluorescence as a Potential Biomarker of Oxidative Damage to the Retina

Różanowska¹

2023

Preprint

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Lipofuscin accumulates with age as intracellular fluorescent granules originating from incomplete lysosomal digestion of phagocytosed and autophagocytosed material. The purpose of this review is to provide an update on the current understanding of the role of oxidative stress and/or lysosomal dysfunction in lipofuscin accumulation and its consequences, particularly for retinal pigment epithelium (RPE). Next, the fluorescence of lipofuscin, spectral changes induced by oxidation, and its contribution to retinal fluorescence are discussed. This is followed by reviewing recent developments in fluorescence imaging of the retina, and the current evidence on the prognostic value of retinal fluorescence for the progression of age-related macular degeneration (AMD), the major blinding disease affecting elderly people in developed countries. The evidence of lipofuscin oxidation in vivo, and the evidence of increased oxidative damage in AMD retina ex vivo lead to the conclusion that imaging of spectral characteristics of lipofuscin fluorescence may serve as a useful biomarker of oxidative damage which can be helpful in assessing the efficacy of potential antioxidant therapies in retinal degenerations associated with accumulation of lipofuscin and increased oxidative stress. Finally, amendments to currently used fluorescence imaging instruments are suggested, to be more sensitive and specific for imaging spectral char-acteristics of lipofuscin fluorescence.

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Spatiotemporal control of actomyosin contractility by MRCKβ signaling drives phagocytosis

Cited by 12 publications

References 66 publications

MRCK activates mouse oocyte myosin II for spindle rotation and male pronucleus centration

MRCK activates mouse oocyte myosin II for spindle rotation and male pronucleus centration

β-actin is essential for structural integrity and physiological function of the retina

Lipofuscin, Its Origin, Properties, and Contribution to Retinal Fluorescence as a Potential Biomarker of Oxidative Damage to the Retina

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