Integrin-Linked Kinase (ILK) Deletion Disrupts Oligodendrocyte Development by Altering Cell Cycle

Hussain, Rashad; Macklin, Wendy B.

doi:10.1523/jneurosci.2113-16.2017

Cited by 3 publications

(3 citation statements)

References 5 publications

(8 reference statements)

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“…Expression of myelin proteins such as MBP and CNPase were reduced in Trem2 Y38C/Y38C and Trem2 -/-. IPA analysis revealed ILK signaling, which is involved in oligodendrocyte development [48], was impacted in both Trem2 Y38C/Y38C and Trem2 -/mice. We observed signi cant reduction in MBP protein expression in the cortical lysates of Trem2 Y38C/Y38C and Trem2 -/mice, further supporting our transcriptomics ndings.…”

Section: Discussionmentioning

confidence: 99%

Trem2 Y38C Mutation and Loss of Trem2 Impairs Neuronal Synapses in Adult Mice

Jadhav

Lin

Pennington

et al. 2020

Preprint

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Background:Triggering receptor expressed on myeloid cells 2 (TREM2) is expressed in the brain exclusively on microglia and genetic variants are linked to neurodegenerative diseases including Alzheimer’s disease (AD), frontotemporal dementia (FTD) and NasuHakola Disease (NHD). The Trem2 variantR47H, confers substantially elevated risk of developing late onset Alzheimer’s disease, while NHD-linkedTrem2 variants like Y38Care associated with development of early onset dementia with white matter pathology. However, it is not known how these Trem2species predispose individuals to presenile dementia.Methods:To investigate if Trem2 Y38C or loss of Trem2 alters neuronal function, we generated a novel mouse model to introduce the NHD Trem2 Y38C variant in murine Trem2 using CRISPR/Cas9 technology. Trem2Y38/Y38C and Trem2-/-mice were assessed for Trem2 expression, differentially expressed genes, synaptic protein levels and synaptic plasticity using biochemical, electrophysiological and transcriptomic approaches.Results:While mice harboring Trem2 Y38C exhibited normal expression levels of Trem2, the pathological outcomes phenocopied Trem2-/- miceat 6 months. Transcriptomic analysis revealed altered expression of neuronal and oligodendrocytes/myelin genes. We observed regional decreases in synaptic protein levels, with the most affected synapses in the hippocampus. These alterations were associated with reduced synaptic plasticity. Conclusion:Our findings provide in vivo evidence that Trem2 Y38C disrupts normal TREM2 functions. Trem2Y38C/Y38Cand Trem2-/- mice demonstrated altered gene expression, changes in microglia morphology, loss of synaptic proteins and reduced hippocampal synaptic plasticity at 6 months in absence of any pathological triggers like tau or amyloid. This suggests TREM2 impacts neuronal functions and providesmolecular insights on the predisposition of individuals with TREM2 variants resulting in presenile dementia.

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Section: Discussionmentioning

confidence: 99%

Trem2 Y38C Mutation and Loss of Trem2 Impairs Neuronal Synapses in Adult Mice

Jadhav

Lin

Pennington

et al. 2020

Preprint

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“…PAK1 also controls Notch signalling through phosphorylating and activating integrin‐linked kinases (ILKs) (Acconcia et al ., 2007) which, in turn, phosphorylates the NICD at Ser2173 and promotes proteosome‐mediated NICD degradation, a process in which the E3 ligase F‐box/WD repeat‐containing protein 7 (Fbxw7) [which tags NICD with ubiquitin (Ub)] plays an essential role (Mo et al ., 2007). ILK, which plays an essential role in tumorigenesis, has been shown to regulate OPC proliferation and differentiation (Hussain & Macklin, 2017). In addition to ILK, NICD is also reported to interact directly with PAK1 and facilitate PAK1 (and/or ILK) nuclear translocation (Yoon et al ., 2016).…”

Section: Group I Paks and Oligodendrocyte Developmentmentioning

confidence: 99%

Group I PAKs in myelin formation and repair of the central nervous system: what, when, and how

Wang

Guo

2021

Biological Reviews

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p21‐activated kinases (PAKs) are a family of cell division control protein 42/ras‐related C3 botulinum toxin substrate 1 (Cdc42/Rac1)‐activated serine/threonine kinases. Group I PAKs (PAK1–3) have distinct activation mechanisms from group II PAKs (PAK4–6) and are the focus of this review. In transformed cancer cells, PAKs regulate a variety of cellular processes and molecular pathways which are also important for myelin formation and repair in the central nervous system (CNS). De novo mutations in group I PAKs are frequently seen in children with neurodevelopmental defects and white matter anomalies. Group I PAKs regulate virtually every aspect of neuronal development and function. Yet their functions in CNS myelination and remyelination remain incompletely defined. Herein, we highlight the current understanding of PAKs in regulating cellular and molecular pathways and discuss the status of PAK‐regulated pathways in oligodendrocyte development. We point out outstanding questions and future directions in the research field of group I PAKs and oligodendrocyte development.

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“…In oligodendrocytes, Ilk is required for laminin-2-induced formation of myelin-like membrane formation (Chun et al, 2003) and regulates process extension by regulating OL actin cytoskeletal dynamics (O’Meara et al, 2013, Michalski et al, 2016). In vivo , Ilk ablation disturbs OPC proliferation and differentiation (Hussain and Macklin, 2017). However, as it prevents assembly of the IPP complex it also leads to the degradation of the other IPP components making it impossible to dissect the exact role played by Pinch1 and 2 in OL development.…”

Section: Introductionmentioning

confidence: 99%

Pinch2 is a novel regulator of myelination in the Central Nervous System

Faria

Vale-Silva

Fässler³

et al. 2022

Preprint

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The extensive morphological changes of oligodendrocytes during axon ensheathment and myelination involve assembly of the Ilk-Parvin-Pinch (IPP) heterotrimeric complex of proteins to relay essential mechanical and biochemical signals between integrins and the actin cytoskeleton. Binding of Pinch 1 and 2 isoforms to Ilk is mutually exclusive and allows the formation of distinct IPP complexes with specific signaling properties. Using tissue-specific conditional gene ablation in mice, we reveal an essential role for Pinch2 during central nervous system myelination. Unlike Pinch1-gene ablation, loss of Pinch2 in oligodendrocytes results in hypermyelination and in the formation of pathological myelin outfoldings in white matter regions. These structural changes concurred with inhibition of Rho GTPases RhoA and Cdc42 activities and phenocopied aspects of myelin pathology observed in corresponding mouse mutants. We propose a dual role for Pinch2 in preventing excess of myelin wraps through RhoA-dependent control of membrane growth and in fostering myelin stability via Cdc42-dependent organization of cytoskeletal septins. Together, these findings indicate that IPP-containing Pinch2 is a novel critical cell-autonomous molecular hub ensuring synchronous control of key signaling networks during developmental myelination.Summary statementPinch proteins are core components of a ternary protein complex comprising Ilk and Parvin (IPP). This work identifies Pinch2 as key regulator of the formation and maturation of CNS myelin.

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Integrin-Linked Kinase (ILK) Deletion Disrupts Oligodendrocyte Development by Altering Cell Cycle

Cited by 3 publications

References 5 publications

Trem2 Y38C Mutation and Loss of Trem2 Impairs Neuronal Synapses in Adult Mice

Trem2 Y38C Mutation and Loss of Trem2 Impairs Neuronal Synapses in Adult Mice

Group I PAKs in myelin formation and repair of the central nervous system: what, when, and how

Pinch2 is a novel regulator of myelination in the Central Nervous System

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