N-WASP is required for membrane wrapping and myelination by Schwann cells

Novak, Nurit; Bar, Vered; Sabanay, Helena; Frechter, Shahar; Jaegle, Martine; Snapper, Scott B.; Meijer, Dies; Peles, Elior

doi:10.1083/jcb.201010013

Cited by 75 publications

(76 citation statements)

References 46 publications

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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%

“…4Bb,d, white arrowheads). The Pfn1 mutant phenotype seemed to resemble that of the SCspecific N-Wasp (Wasl -Mouse Genome Informatics) mutant mouse (Jin et al, 2011;Novak et al, 2011), in which the diminished capacity of SCs to form lamellipodia at later stages affected mainly the ability to enwrap axons. This differed from the integrin β1 ( Ilk (Pereira et al, 2009) SC-conditional mutant mice, in which defects in radial lamellipodia formation affected mainly the capacity of SCs to sort axons, resulting in persistent sorting defects.…”

Section: Research Articlementioning

confidence: 99%

“…In neurons and in other cell types, Pfn is thought to participate in the reorganization of the actin cytoskeleton by binding to actin and to a plethora of cytoskeleton-regulating proteins with proline-rich domains, such as Ena/Mena/VASP family members, and N-WASP, which, as mentioned above, has recently been implicated in radial sorting (Jin et al, 2011;Novak et al, 2011). Pfn can also directly bind to membrane phospholipids, mainly PtdIns(4,5)P 2 [phosphatidylinositol (4,5)-bisphosphate] and PtdIns(3,4,5)P 3 (Lassing and Lindberg, 1985), linking lipid-based signaling pathways to the actin cytoskeleton (Birbach, 2008).…”

Section: Pfn1 Regulates Sc Radial Lamellipodia Independently Of Rac1mentioning

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%

“…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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Section: Discussionmentioning

confidence: 99%

Section: Research Articlementioning

confidence: 99%

Section: Pfn1 Regulates Sc Radial Lamellipodia Independently Of Rac1mentioning

confidence: 99%

Section: Pfn1 Regulates Sc Radial Lamellipodia Independently Of Rac1mentioning

confidence: 99%

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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Variation in SIPA1L2 is correlated with phenotype modification in Charcot– Marie– Tooth disease type 1A

Tao

Beecham

Rebelo

et al. 2019

Annals of Neurology

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Objective: Genetic modifiers in rare disease have long been suspected to contribute to the considerable variance in disease expression, including Charcot-Marie-Tooth disease type 1A (CMT1A). To address this question, the Inherited Neuropathy Consortium collected a large standardized sample of such rare CMT1A patients over a period of 8 years. CMT1A is caused in most patients by a uniformly sized 1.5 Mb duplication event involving the gene PMP22. Methods: We genotyped DNA samples from 971 CMT1A patients on Illumina BeadChips. Genome-wide analysis was performed in a subset of 330 of these patients, who expressed the extremes of a hallmark symptom: mild and severe foot dorsiflexion strength impairment. SIPA1L2 (signal-induced proliferation-associated 1 like 2), the top identified candidate modifier gene, was expressed in the peripheral nerve, and our functional studies identified and confirmed interacting proteins using coimmunoprecipitation analysis, mass spectrometry, and immunocytochemistry. Chromatin immunoprecipitation and in vitro siRNA experiments were used to analyze gene regulation. Results: We identified significant association of 4 single nucleotide polymorphisms (rs10910527, rs7536385, rs4649265, rs1547740) in SIPA1L2 with foot dorsiflexion strength (p < 1 × 10 −7 ). Coimmunoprecipitation and mass spectroscopy studies identified β-actin and MYH9 as SIPA1L2 binding partners. Furthermore, we show that SIPA1L2 is part of a View this article online at wileyonlinelibrary.com.

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Genetic disruption of Pten in a novel mouse model of tomaculous neuropathy

et al. 2012

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‘Tomacula’ and myelin outfoldings are striking neuropathological features of a diverse group of inherited demyelinating neuropathies. Whereas the underlying genetic defects are well known, the molecular mechanisms of tomacula formation have remained obscure. We hypothesized that they are caused by uncontrolled, excessive myelin membrane growth, a process, which is regulated in normal development by neuregulin-1/ErbB2, PI3 Kinase signalling and ERK/MAPK signalling. Here, we demonstrate by targeted disruption of Pten in Schwann cells that hyperactivation of the endogenous PI3 Kinase pathway causes focal hypermyelination, myelin outfoldings and tomacula, even when induced in adult animals by tamoxifen, and is associated with progressive peripheral neuropathy. Activated AKT kinase is associated with PtdIns(3,4,5)P3 at paranodal loops and Schmidt–Lanterman incisures. This striking myelin pathology, with features of human CMT type 4B1 and HNPP, is dependent on AKT/mTOR signalling, as evidenced by a significant amelioration of the pathology in mice treated with rapamycin. We suggest that regions of non-compact myelin are under lifelong protection by PTEN against abnormal membrane outgrowth, and that dysregulated phosphoinositide levels play a critical role in the pathology of tomaculous neuropathies.

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N-WASP is required for membrane wrapping and myelination by Schwann cells

Abstract: N-WASP–deficient Schwann cells sort and ensheath axons but arrest at the promyelinating stage.

Cited by 75 publications

References 46 publications

Profilin 1 is required for peripheral nervous system myelination

Profilin 1 is required for peripheral nervous system myelination

Variation in SIPA1L2 is correlated with phenotype modification in Charcot– Marie– Tooth disease type 1A

Genetic disruption of Pten in a novel mouse model of tomaculous neuropathy

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