MLCK regulates Schwann cell cytoskeletal organization, differentiation and myelination

Leitman, Ellen M.; Tewari, Ambika; Horn, Meryl; Urbanski, Mateusz M.; Damanakis, Evangelos; Einheber, Steven; Salzer, James L.; Lanerolle, Primal de; Melendez‐Vasquez, Carmen V.

doi:10.1242/dev.077297

Cited by 5 publications

(8 citation statements)

References 41 publications

(54 reference statements)

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“…Alpha‐Parvin‐deficient vascular smooth muscle cells fail to polarize their cytoskeleton, resulting in loss of persistent and directed migration (Montanez et al, ). Another study showed that knockdown of MLCK in Schwann cells induced plasma membrane expansion (Leitman et al, ). In this study, we detected the up‐regulation of the MLCP gene (PPP1R12A gene) and down‐regulation of the MLCK gene (MYLK gene).…”

Section: Discussionmentioning

confidence: 99%

Exploration of molecular pathways mediating electric field-directed schwann cell migration by RNA-seq

Yao

Knapp

et al. 2015

J. Cell. Physiol.

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In peripheral nervous systems, Schwann cells wrap around axons of motor and sensory neurons to form the myelin sheath. Following spinal cord injury, Schwann cells regenerate and migrate to the lesion and are involved in the spinal cord regeneration process. Transplantation of Schwann cells into injured neural tissue results in enhanced spinal axonal regeneration. Effective directional migration of Schwann cells is critical in the neural regeneration process. In this study, we report that Schwann cells migrate anodally in an applied electric field (EF). The directedness and displacement of anodal migration increased significantly when the strength of the EF increased from 50 mV/mm to 200 mV/mm. The EF did not significantly affect the cell migration speed. To explore the genes and signaling pathways that regulate cell migration in EFs, we performed a comparative analysis of differential gene expression between cells stimulated with an EF (100 mV/mm) and those without using next-generation RNA sequencing, verified by RT-qPCR. Based on the cut-off criteria (FC > 1.2, q < 0.05), we identified 1,045 up-regulated and 1,636 down-regulated genes in control cells versus EF-stimulated cells. A Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis found that compared to the control group, 21 pathways are down-regulated, while 10 pathways are up-regulated. Differentially expressed genes participate in multiple cellular signaling pathways involved in the regulation of cell migration, including pathways of regulation of actin cytoskeleton, focal adhesion, and PI3K-Akt.

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Section: Discussionmentioning

confidence: 99%

Exploration of molecular pathways mediating electric field-directed schwann cell migration by RNA-seq

Yao

Knapp

et al. 2015

J. Cell. Physiol.

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“…They depend on laminin/integrin β1 interactions (Feltri et al, 2002), downstream activation of the small RhoGTPase Rac1 (Benninger et al, 2007;Nodari et al, 2007) via lymphoid cell kinase phosphorylation (Ness et al, 2013), and regulation of its targets N-WASP (Jin et al, 2011;Novak et al, 2011) and MLCK/myosin II (Wang et al, 2008;Leitman et al, 2011). Together with the negative regulation of Rho/ROCK signaling by Ilk (Pereira et al, 2009), they control SC cytoskeleton reorganization and the formation of SC lamellipodia largely through not yet fully characterized downstream targets and functional mechanisms.…”

Section: Discussionmentioning

confidence: 99%

“…6). Such pathways control several cytoskeleton modulators, including N-WASP (Tomasevic et al, 2007;Jin et al, 2011;Novak et al, 2011) and MLCK/myosin II (Wang et al, 2008;Leitman et al, 2011), that are key in regulating radial lamellipodia formation, an essential requirement for radial sorting and axon ensheathing. Although Rac1 is a positive regulator, promoting radial lamellipodia and radial sorting, Rho/ROCK can counteract it as a negative regulator, repressing their formation.…”

Section: Pfn1 Regulates Sc Radial Lamellipodia Independently Of Rac1mentioning

confidence: 99%

“…These processes are co-regulated by integrin β1 (Feltri et al, 2002), which activates (blue line) Rac1 (Benninger et al, 2007;Nodari et al, 2007) mainly via laminin/integrin-β1/lymphoid cell kinase (LCK) tyrosine kinase (Ness et al, 2013) also modulating the activity of cytoskeletal remodeling proteins, e.g. MLCK/myosin II (Wang et al, 2008;Leitman et al, 2011) and N-Wasp (Jin et al, 2011;Novak et al, 2011). These are crucial in mediating lamellipodia formation and SC myelination.…”

Section: Generation Of Conditional Knockout Micementioning

confidence: 99%

“…Whereas Cdc42 is mainly involved in the control of SC proliferation (Benninger et al, 2007), Rac1 promotes SC lamellipodia formation (Benninger et al, 2007;Nodari et al, 2007) downstream of laminin/integrin-β1/lymphoid cell kinase (LCK) (Feltri et al, 2002;Ness et al, 2013). Rac1 downstream targets N-WASP (Jin et al, 2011;Novak et al, 2011) and MLCK/myosin II (Wang et al, 2008;Leitman et al, 2011) are key regulators of radial sorting and PNS myelination. Negative regulation of Rho/ROCK signaling by integrin-linked kinase (Ilk) (Pereira et al, 2009) is also strictly required for SC cytoskeleton rearrangements leading to efficient radial sorting.…”

Section: Introductionmentioning

confidence: 99%

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Profilin 1 is required for peripheral nervous system myelination

Montani

Buerki-Thurnherr

Faria³

et al. 2014

Development

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Myelination allows rapid saltatory propagation of action potentials along the axon and is an essential prerequisite for the normal functioning of the nervous system. During peripheral nervous system (PNS) development, myelin-forming Schwann cells (SCs) generate radial lamellipodia to sort and ensheath axons. This process requires controlled cytoskeletal remodeling, and we show that SC lamellipodia formation depends on the function of profilin 1 (Pfn1), an actinbinding protein involved in microfilament polymerization. Pfn1 is inhibited upon phosphorylation by ROCK, a downstream effector of the integrin linked kinase pathway. Thus, a dramatic reduction of radial lamellipodia formation is observed in SCs lacking integrinlinked kinase or treated with the Rho/ROCK activator lysophosphatidic acid. Knocking down Pfn1 expression by lentiviralmediated shRNA delivery impairs SC lamellipodia formation in vitro, suggesting a direct role for this protein in PNS myelination. Indeed, SC-specific gene ablation of Pfn1 in mice led to profound radial sorting and myelination defects, confirming a central role for this protein in PNS development. Our data identify Pfn1 as a key effector of the integrin linked kinase/Rho/ROCK pathway. This pathway, acting in parallel with integrin β1/LCK/Rac1 and their effectors critically regulates SC lamellipodia formation, radial sorting and myelination during peripheral nervous system maturation.

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Glial progenitor cells of the adult human white and grey matter are contextually distinct

Osorio

Mariani

Zou

et al. 2022

Glia

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Genomic analyses have revealed heterogeneity among glial progenitor cells (GPCs), but the compartment selectivity of human GPCs (hGPCs) is unclear. Here, we asked if GPCs of human grey and white brain matter are distinct in their architecture and associated gene expression. RNA profiling of NG2-defined hGPCs derived from adult human neocortex and white matter differed in their expression of genes involved in Wnt, NOTCH, BMP and TGFβ signaling, suggesting compartment-selective biases in fate and self-renewal. White matter hGPCs over-expressed the BMP antagonists BAMBI and CHRDL1, suggesting their tonic suppression of astrocytic fate relative to cortical hGPCs, whose relative enrichment of cytoskeletal genes presaged their greater morphological complexity. In human glial chimeric mice, cortical hGPCs assumed larger and more complex morphologies than white matter hGPCs, and both were more complex than their mouse counterparts. These findings suggest that human grey and white matter GPCs comprise context-specific pools with distinct functional biases.glial heterogeneity, human glial progenitor cells, NG2, white and grey matter | INTRODUCTIONGlial progenitor cells (GPCs) comprise 3%-4% of all cells in the human brain (Roy et al., 1999;Scolding et al., 1998). They can be identified based on the expression of gangliosides recognized by the monoclonal antibody (mAb) A2B5 (Roy et al., 1999;Scolding et al., 1998), by chondroitin sulfate proteoglycan 4 as recognized by mAb NG2, and by the CD140a epitope of PDGF receptor alpha (PDGFRa) (Sim et al., 2011).GPCs are the source of mature oligodendrocytes in the adult human brain, and are required for both myelin turnover and repair of demyelinated lesions. As such, they are operationally synonymous with oligodendrocyte progenitor cells (OPCs) and NG2 cells (Suzuki & Nishiyama, 2009). Yet these cells are bipotential for astrocytes as well

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MLCK regulates Schwann cell cytoskeletal organization, differentiation and myelination

Cited by 5 publications

References 41 publications

Exploration of molecular pathways mediating electric field-directed schwann cell migration by RNA-seq

Exploration of molecular pathways mediating electric field-directed schwann cell migration by RNA-seq

Profilin 1 is required for peripheral nervous system myelination

Glial progenitor cells of the adult human white and grey matter are contextually distinct

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