Gene-Silencing Screen for Mammalian Axon Regeneration Identifies Inpp5f (Sac2) as an Endogenous Suppressor of Repair after Spinal Cord Injury

Zou, Yixiao; Stagi, Massimiliano; Wang, Xingxing; Yiğitkanlı, Kazım; Siegel, Chad; Nakatsu, Fubito; Cafferty, William B. J.; Strittmatter, Stephen M.

doi:10.1523/jneurosci.1718-15.2015

Cited by 34 publications

(49 citation statements)

References 52 publications

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“…We conducted a loss of function genome-wide in vitro axon regeneration screen in primary mouse cortical neurons (Huebner et al, 2011; Zou et al, 2015). We reasoned that this in vitro model, although lacking features of the in vivo CNS such as environmental contributions from glia and matrix, would capture cell-intrinsic functions of CNS neurons that limit regeneration.…”

Section: Resultsmentioning

confidence: 99%

“…Semaphorins, as extracellular cues inhibiting extension and collapsing growth cones, stimulate local and massive macropinocytosis at the growth cone (Fournier et al, 2000). Inpp5f regulates both axon regeneration and membrane traffic (Nakatsu et al, 2015; Zou et al, 2015). In C. elegans , loss of function in any of three endocytosis genes ( unc-26 /synaptojanin, unc-57 /endophilin, and unc-41 /stonin) results in decreased regeneration (Chen et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

“…With single clones spanning a lentiviral short hairpin RNA (shRNA) library, we assessed the role of each gene to limit axonal regeneration. Our pilot screen restricted to 219 phosphatases had uncovered a role for Inpp5f in limiting axonal regrowth and neurological recovery from trauma (Zou et al, 2015). Here, a comprehensive genome-wide screen reveals about 500 genes with a regeneration phenotype, and the vast majority were not previously identified by expression surveys or previous limited functional studies.…”

Section: Introductionmentioning

confidence: 99%

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Functional Genome-wide Screen Identifies Pathways Restricting Central Nervous System Axonal Regeneration

et al. 2018

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SUMMARY Axonal regrowth is crucial for recovery from CNS injury but is severely restricted in adult mammals. We used a genome-wide loss-of-function screen for factors limiting axonal regeneration from cerebral cortical neurons in vitro. Knockdown of 16,007 individual genes identified 580 significant phenotypes. These molecules share no significant overlap with those suggested by previous expression profiles. There is enrichment for genes in pathways related to transport, receptor binding, and cytokine signaling, including Socs4 and Ship2. Among transport-regulating proteins, Rab GTPases are prominent. In vivo assessment with C. elegans validates a cell-autonomous restriction of regeneration by Rab27. Mice lacking Rab27b show enhanced retinal ganglion cell axon regeneration after optic nerve crush and greater motor function and raphespinal sprouting after spinal cord trauma. Thus, a comprehensive functional screen reveals multiple pathways restricting axonal regeneration and neurological recovery after injury.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Functional Genome-wide Screen Identifies Pathways Restricting Central Nervous System Axonal Regeneration

et al. 2018

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“…Axon order in central nervous system (CNS) tracts has been newly revisited on an anatomical and molecular basis, with the implication that pretarget organization is necessary for proper innervation into target laminae or subzones (e.g., Imai et al, 2009;Zhou et al, 2013). In the optic tract, RGC axons are organized chronotopically, retinotopically, by laterality of projection (ipsilateral vs contralateral), and by functional type (Torrealba et al, 1982;Guillery and Walsh, 1987;Chan and Guillery, 1994;Plas et al, 2005).…”

Section: State Of the Fieldmentioning

confidence: 99%

“…For example, inhibitors of protein prenylation, such as statins, can accelerate axon growth in an optic nerve crush model and can also implement axon sprouting at the neuromuscular junction, an inroad into therapies for ALS . In a similar vein, an unbiased RNAi gene-silencing screen has revealed that Inpp5f (Sac2) is a phosphatase suppressor of injury-induced CNS axon growth (Zou et al, 2015). Rtca (RNA 3Ј-terminal phosphate cyclase) is an inhibitor of axon regeneration and, when blocked, can implement regeneration in Drosophila and in the mouse retinal axon pathway (Song et al, 2015).…”

Section: Plasticity In Upstream Circuits (Dlgn and Cortex) Could Be Cmentioning

confidence: 99%

Reconnecting Eye to Brain

Crair

Mason

2016

J. Neurosci.

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Although much is known about the regenerative capacity of retinal ganglion cells, very significant barriers remain in our ability to restore visual function following traumatic injury or disease-induced degeneration. Here we summarize our current understanding of the factors regulating axon guidance and target engagement in regenerating axons, and review the state of the field of neural regeneration, focusing on the visual system and highlighting studies using other model systems that can inform analysis of visual system regeneration. This overview is motivated by a Society for Neuroscience Satellite meeting, "Reconnecting Neurons in the Visual System," held in October 2015 sponsored by the National Eye Institute as part of their "Audacious Goals Initiative" and co-organized by Carol Mason (Columbia University) and Michael Crair (Yale University). The collective wisdom of the conference participants pointed to important gaps in our knowledge and barriers to progress in promoting the restoration of visual system function. This article is thus a summary of our existing understanding of visual system regeneration and provides a blueprint for future progress in the field.

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Identification of Intrinsic Axon Growth Modulators for Intact CNS Neurons after Injury

et al. 2017

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SUMMARY Functional deficits persist after spinal cord injury (SCI) because axons in the adult mammalian central nervous system (CNS) fail to regenerate. However, modest levels of spontaneous functional recovery are typically observed after trauma and are thought to be mediated by the plasticity of intact circuitry. The mechanisms underlying intact circuit plasticity are not delineated. Here, we characterize the in vivo transcriptome of sprouting intact neurons from Ngr1 null mice after partial SCI. We identify the lysophosphatidic acid signaling modulators LPPR1 and LPAR1 as intrinsic axon growth modulators for intact corticospinal motor neurons after adjacent injury. Furthermore, in vivo LPAR1 inhibition or LPPR1 overexpression enhances sprouting of intact corticospinal tract axons and yields greater functional recovery after unilateral brainstem lesion in wild-type mice. Thus, the transcriptional profile of injury-induced sprouting of intact neurons reveals targets for therapeutic enhancement of axon growth initiation and new synapse formation.

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Gene-Silencing Screen for Mammalian Axon Regeneration Identifies Inpp5f (Sac2) as an Endogenous Suppressor of Repair after Spinal Cord Injury

Cited by 34 publications

References 52 publications

Functional Genome-wide Screen Identifies Pathways Restricting Central Nervous System Axonal Regeneration

Functional Genome-wide Screen Identifies Pathways Restricting Central Nervous System Axonal Regeneration

Reconnecting Eye to Brain

Identification of Intrinsic Axon Growth Modulators for Intact CNS Neurons after Injury

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