Ral GTPases in Schwann cells promote radial axonal sorting in the peripheral nervous system

Ommer, Andrea; Figlia, Gianluca; Pereira, Jorge A.; Datwyler, Anna Lena; Gerber, Joanne; DeGeer, Jonathan; Lalli, Giovanna; Suter, Ueli

doi:10.1083/jcb.201811150

Cited by 13 publications

(9 citation statements)

References 68 publications

(120 reference statements)

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“…In this work, we found that cell-autonomous manipulation of the levels of RalA GTPase in wrapping glia leads to severe defects in axon ensheathment and that Rala mutants have locomotor deficits, supporting an important physiological role of RalA GTPase for the control of movement. Interestingly, two recent papers reported that RalA GTPase and the exocyst are required in Schwann cells during axonal sorting and in nerve repair by regulating Schwann cell process formation, migration and myelination (Galino et al, 2019;Ommer et al, 2019). These studies support our data concerning the involvement of RalA in glial regulation of axonal ensheathment.…”

Section: Discussionsupporting

confidence: 89%

Peripheral axonal ensheathment is regulated by RalA GTPase and the exocyst complex

et al. 2020

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Axon ensheathment is fundamental for fast impulse conduction and the normal physiological functioning of the nervous system. Defects in axonal insulation lead to debilitating conditions, but despite its importance, the molecular players responsible are poorly defined. Here, we identify Ral GTPase as a key player in axon ensheathment in Drosophila larval peripheral nerves. We demonstrate through genetic analysis that Ral action through the exocyst complex is required in wrapping glial cells to regulate their growth and development. We suggest that the Ral-exocyst pathway controls the targeting of secretory vesicles for membrane growth or for the secretion of a wrapping glia-derived factor that itself regulates growth. In summary, our findings provide a new molecular understanding of the process by which axons are ensheathed in vivo, a process critical for normal neuronal function.

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Section: Discussionsupporting

confidence: 89%

Peripheral axonal ensheathment is regulated by RalA GTPase and the exocyst complex

et al. 2020

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“…Without such a splitting, the RNA-seq data reflect an average signal between the two populations as seen in the allSC gating strategy that includes all eYFP-positive SCs ( Figure 2B,C ), yielding a convoluted picture of SC transcription dynamics around the onset of myelination. We anticipate that the described experimental strategy will be particularly valuable in the evaluation of the molecular phenotypes of mouse mutants that affect axonal radial sorting by SCs and the onset of myelination ( Figlia et al, 2017 ; Gerber et al, 2019 ; Grove and Brophy, 2014 ; Nodari et al, 2007 ; Ommer et al, 2019 ; Porrello et al, 2014 ). Furthermore, our RNA-seq data of the different FACS-selected SC populations expand significantly the transcriptome resource SNAT for SC-targeted data mining.…”

Section: Resultsmentioning

confidence: 99%

Transcriptional profiling of mouse peripheral nerves to the single-cell level to build a sciatic nerve ATlas (SNAT)

Gerber

Pereira

Gerber

et al. 2021

eLife

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129

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Peripheral nerves are organ-like structures containing diverse cell types to optimize function. This interactive assembly includes mostly axon-associated Schwann cells, but also endothelial cells of supporting blood vessels, immune system-associated cells, barrier-forming cells of the perineurium surrounding and protecting nerve fascicles, and connective tissue-resident cells within the intra-fascicular endoneurium and inter-fascicular epineurium. We have established transcriptional profiles of mouse sciatic nerve-inhabitant cells to foster the fundamental understanding of peripheral nerves. To achieve this goal, we have combined bulk RNA sequencing of developing sciatic nerves up to the adult with focused bulk and single-cell RNA sequencing of Schwann cells throughout postnatal development, extended by single-cell transcriptome analysis of the full sciatic nerve both perinatally and in the adult. The results were merged in the transcriptome resource Sciatic Nerve ATlas (SNAT:https://www.snat.ethz.ch). We anticipate that insights gained from our multi-layered analysis will serve as valuable interactive reference point to guide future studies.

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“…Rho GTPases: small GTPases of the Rho (e.g., Cdc42, RhoA, Rac1) and Ras (RalA, RalB) families act as molecular switches, shuttling between activated GTP-bound and inactive GDP-bound states. Rho and Ras GTPases regulate cytoskeletal organization in Schwann cells to modulate critical events such as radial sorting during development (Benninger et al, 2007 ; Guo et al, 2013 ; Tan et al, 2018 ; Ommer et al, 2019 ). The chronic lack of Ral proteins in Schwann cells impairs radial sorting, resulting in the formation of unmyelinated or hypo-myelinated large-caliber axons, and abnormalities in the myelin sheath (Ommer et al, 2019 ).…”

Section: Schwann Cells: Understanding Development To Engineer Repairmentioning

confidence: 99%

“…Rho and Ras GTPases regulate cytoskeletal organization in Schwann cells to modulate critical events such as radial sorting during development (Benninger et al, 2007 ; Guo et al, 2013 ; Tan et al, 2018 ; Ommer et al, 2019 ). The chronic lack of Ral proteins in Schwann cells impairs radial sorting, resulting in the formation of unmyelinated or hypo-myelinated large-caliber axons, and abnormalities in the myelin sheath (Ommer et al, 2019 ). Similarly, the large GTPase Dynamin2 ( Dnm2 ) is also required for Schwann cell survival, radial sorting, and myelination (Gerber et al, 2019 ).…”

Section: Schwann Cells: Understanding Development To Engineer Repairmentioning

confidence: 99%

Insights Into the Role and Potential of Schwann Cells for Peripheral Nerve Repair From Studies of Development and Injury

Balakrishnan

Belfiore

Chu

et al. 2021

Front. Mol. Neurosci.

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Peripheral nerve injuries arising from trauma or disease can lead to sensory and motor deficits and neuropathic pain. Despite the purported ability of the peripheral nerve to self-repair, lifelong disability is common. New molecular and cellular insights have begun to reveal why the peripheral nerve has limited repair capacity. The peripheral nerve is primarily comprised of axons and Schwann cells, the supporting glial cells that produce myelin to facilitate the rapid conduction of electrical impulses. Schwann cells are required for successful nerve regeneration; they partially “de-differentiate” in response to injury, re-initiating the expression of developmental genes that support nerve repair. However, Schwann cell dysfunction, which occurs in chronic nerve injury, disease, and aging, limits their capacity to support endogenous repair, worsening patient outcomes. Cell replacement-based therapeutic approaches using exogenous Schwann cells could be curative, but not all Schwann cells have a “repair” phenotype, defined as the ability to promote axonal growth, maintain a proliferative phenotype, and remyelinate axons. Two cell replacement strategies are being championed for peripheral nerve repair: prospective isolation of “repair” Schwann cells for autologous cell transplants, which is hampered by supply challenges, and directed differentiation of pluripotent stem cells or lineage conversion of accessible somatic cells to induced Schwann cells, with the potential of “unlimited” supply. All approaches require a solid understanding of the molecular mechanisms guiding Schwann cell development and the repair phenotype, which we review herein. Together these studies provide essential context for current efforts to design glial cell-based therapies for peripheral nerve regeneration.

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Ral GTPases in Schwann cells promote radial axonal sorting in the peripheral nervous system

Cited by 13 publications

References 68 publications

Peripheral axonal ensheathment is regulated by RalA GTPase and the exocyst complex

Peripheral axonal ensheathment is regulated by RalA GTPase and the exocyst complex

Transcriptional profiling of mouse peripheral nerves to the single-cell level to build a sciatic nerve ATlas (SNAT)

Insights Into the Role and Potential of Schwann Cells for Peripheral Nerve Repair From Studies of Development and Injury

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