<scp><i>Kif3a</i></scp> deletion prevents primary cilia assembly on oligodendrocyte progenitor cells, reduces oligodendrogenesis and impairs fine motor function

Cullen, Carlie L.; O’Rourke, Megan E.; Beasley, Shannon J.; Auderset, Loic; Zhen, Yilan; Pepper, Renee E; Gasperini, Robert; Young, Karen

doi:10.1002/glia.23957

Cited by 14 publications

(40 citation statements)

References 116 publications

(179 reference statements)

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“…It was further found that primary cilia of OPCs were disassembled during differentiation into OLGs ( Falcon-Urrutia et al, 2015 ). Notably, in a mouse model, depletion of KIF3A in OPCs inhibited OLG proliferation and differentiation by affecting cilia-dependent Shh signaling and subsequently induced motor defects due to a decrease in myelinated axons ( Cullen et al, 2021 ). Interestingly, the abnormal length of primary cilia in OPCs led to impairment of OLG differentiation ( Dugas et al, 2010 ; Hudish et al, 2016 ).…”

Section: Primary Cilium In Oligodendrocytes: a Key Mediator For Myelination In The Central Nervous Systemmentioning

confidence: 99%

Primary Cilia in Glial Cells: An Oasis in the Journey to Overcoming Neurodegenerative Diseases

Jeong

Lee

2021

Front. Neurosci.

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Many neurodegenerative diseases have been associated with defects in primary cilia, which are cellular organelles involved in diverse cellular processes and homeostasis. Several types of glial cells in both the central and peripheral nervous systems not only support the development and function of neurons but also play significant roles in the mechanisms of neurological disease. Nevertheless, most studies have focused on investigating the role of primary cilia in neurons. Accordingly, the interest of recent studies has expanded to elucidate the role of primary cilia in glial cells. Correspondingly, several reports have added to the growing evidence that most glial cells have primary cilia and that impairment of cilia leads to neurodegenerative diseases. In this review, we aimed to understand the regulatory mechanisms of cilia formation and the disease-related functions of cilia, which are common or specific to each glial cell. Moreover, we have paid close attention to the signal transduction and pathological mechanisms mediated by glia cilia in representative neurodegenerative diseases. Finally, we expect that this field of research will clarify the mechanisms involved in the formation and function of glial cilia to provide novel insights and ideas for the treatment of neurodegenerative diseases in the future.

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Section: Primary Cilium In Oligodendrocytes: a Key Mediator For Myelination In The Central Nervous Systemmentioning

confidence: 99%

Primary Cilia in Glial Cells: An Oasis in the Journey to Overcoming Neurodegenerative Diseases

Jeong

Lee

2021

Front. Neurosci.

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“…proliferation, as suggested by Cullen et al (2020). However, this result also suggests that PC could be implicated in transition from proliferative to differentiating stages.…”

Section: Discussionmentioning

confidence: 49%

Oligodendroglial primary cilium heterogeneity during development and demyelination/remyelination

Delfino

Bénardais²,

Graff³

et al. 2022

Front. Cell. Neurosci.

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The primary cilium (PC) has emerged as an indispensable cellular antenna essential for signal transduction of important cell signaling pathways. The rapid acquisition of knowledge about PC biology has raised attention to PC as a therapeutic target in some neurological and psychiatric diseases. However, the role of PC in oligodendrocytes and its participation in myelination/remyelination remain poorly understood. Oligodendrocyte precursor cells (OPCs) give rise to oligodendrocytes during central nervous system (CNS) development. In adult, a small percentage of OPCs remains as undifferentiated cells located sparsely in the different regions of the CNS. These cells can regenerate oligodendrocytes and participate to certain extent in remyelination. This study aims characterize PC in oligodendrocyte lineage cells during post-natal development and in a mouse model of demyelination/remyelination. We show heterogeneity in the frequency of cilium presence on OPCs, depending on culture conditions in vitro and cerebral regions in vivo during development and demyelination/remyelination. In vitro, Lithium chloride (LiCl), Forskolin and Chloral Hydrate differentially affect cilium, depending on culture environment and PC length correlates with the cell differentiation state. Beside the role of PC as a keeper of cell proliferation, our results suggest its involvement in myelination/remyelination.

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“…To identify new components involved in Hh signaling transduction, we isolated the mouse embryonic fibroblasts (MEFs) and seeded them in different densities to make MEFs deciliated or ciliated and biochemically extracted total membrane proteins from the deciliated MEFs in low densities as well as the ciliated MEFs in high densities (Figure 1 A-B). Data of liquid chromatography-tandem mass spectrometry (LC-MS/MS) with normalization to protein content revealed that, compared with the deciliated MEFs, the ciliated MEFs are enriched in acetylated tubulin (Ac-Tub) and Arl13b, two markers for primary cilia 23 , 24 , and IFT88 and KIF3A as well, two molecules pivotal to the maintenance and function of primary cilia 25 , 26 (Figure 1 C). Intriguingly, among the three members in Rho family of small GTPases 27 , only enrichment of Rac1 but not Cdc42 or RhoA was observed in the ciliated MEFs, compared with that in deciliated MEFs (Figure 1 C), and the enrichment of Rac1 in MEF primary cilia was additionally verified by immunnofluorescent staining (Figure 1 D), indicating that Rac1 may affect Hh signaling.…”

Section: Resultsmentioning

confidence: 99%

Hedgehog signaling is controlled by Rac1 activity

Tang¹,

Wu²,

Ren³

et al. 2022

Theranostics

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Rationale: The nuclear translocation of transcriptional factor Gli is indispensable for Hedgehog (Hh) signaling activation, whose deregulation causes cancer progressions; however, the mechanisms governing Gli nuclear translocation are poorly understood. Here, we report that the Gli translocation in response to Hh requires Rac1 activation. Methods: C3H10T1/2 cell line and mouse embryonic fibroblasts were used to explore the molecular mechanisms underlying Rac1 activity in regulation of Hh signaling transduction. Transgenic mouse strains and human medulloblastoma (MB) tissue samples were utilized to examine the role of Rac1 in Hh-directed limb bud development and MB progression. Results: We show that upon the binding of Hh to receptor Patched1 (Ptch1), receptor Smoothened (Smo) dissociates from Ptch1 and binds to Vav2, resulting in the increased phosphorylation levels of Vav2 at Y172, which further activates Rac1. The role of Rac1 is dependent on the regulation of phosphorylation levels of KIF3A at S689 and T694, which in turn affects IFT88 stability and subsequently dampens SuFu-Gli complex formation, leading to the release of Gli from the complex and the consequent translocation of Gli into the nucleus. Moreover, Vav2 phospho-Y172 levels are up-regulated in GFAP-Cre;SmoM2 +/- mouse cerebellum and human Shh type MB tissues, whereas deficiency of Rac1 in mouse embryonic limb bud ectoderm ( Prx1-Cre;Rac1 f/f ) impedes Hh activation by disruption of Gli nuclear translocation. Conclusion: Together, our results uncover the Rac1 activation and the subsequent Gli translocation as a hitherto uncharacterized mechanism controlling Hh signaling and may provide targets for therapeutic intervention of this signaling pathway.

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Kif3a deletion prevents primary cilia assembly on oligodendrocyte progenitor cells, reduces oligodendrogenesis and impairs fine motor function

Cited by 14 publications

References 116 publications

Primary Cilia in Glial Cells: An Oasis in the Journey to Overcoming Neurodegenerative Diseases

Primary Cilia in Glial Cells: An Oasis in the Journey to Overcoming Neurodegenerative Diseases

Oligodendroglial primary cilium heterogeneity during development and demyelination/remyelination

Hedgehog signaling is controlled by Rac1 activity

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