Robust Axonal Regeneration Occurs in the Injured CAST/Ei Mouse CNS

Ômura, Takao; Omura, Kumiko; Tedeschi, Andrea; Riva, Priscilla; Painter, Michio W.; Rojas, Leticia; Martín, Julio Lumbreras; Lisi, Véronique; Huebner, Eric A.; Latrémolière, Alban; Yin, Yuqin; Barrett, Lee; Singh, Bhagat; Lee, Stella; Crisman, Thomas J.; Gao, Fuying; Li, Songlin; Kapur, Kush; Geschwind, Daniel H.; Kosik, Kenneth S.; Coppola, Giovanni; He, Zhigang; Carmichael, S. Thomas; Benowitz, Larry I.; Costigan, Michael; Woolf, Clifford J.

doi:10.1016/j.neuron.2016.04.025

Cited by 15 publications

(17 citation statements)

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“…Similarly, our meta-analysis of published transcriptome profiling data (Chandran et al 2016;Omura et al 2016) suggest that Ptbp1 is up-regulated in DRG sensory neurons after sciatic nerve lesion, and its expression is also highly correlated with the extent of axonal growth of injured DRG sensory axons. Thus possibly, reduction of Rbfox expression or increase in Ptbp1 may transiently enable a more immature splicing program in these injured neurons to promote axon regrowth.…”

Section: Discussionsupporting

confidence: 60%

Precise temporal regulation of alternative splicing during neural development

Weyn-Vanhentenryck

Feng

Ustianenko

et al. 2018

Preprint

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Alternative splicing (AS) is a crucial step of gene expression that must be tightly controlled, but the precise timing of dynamic splicing switches during neural development and the underlying regulatory mechanisms are poorly understood. Here we systematically analyzed the temporal regulation of AS in a large number of transcriptome profiles of developing mouse cortices, in vivo purified neuronal subtypes, and neurons differentiated in vitro. Our analysis revealed early-and late-switch exons in genes with distinct functions, and these switches accurately define neuronal maturation stages. Integrative modeling suggests that these switches are under direct and combinatorial regulation by distinct sets of neuronal RNA-binding proteins including Nova, Rbfox, Mbnl and Ptbp. Surprisingly, various neuronal subtypes in the sensory systems lack Nova and/or Rbfox expression. These neurons retain the "immature" splicing program in early-switch exons, affecting numerous synaptic genes. These results provide new insights into the organization and regulation of the neurodevelopmental transcriptome.

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Section: Discussionsupporting

confidence: 60%

Precise temporal regulation of alternative splicing during neural development

Weyn-Vanhentenryck

Feng

Ustianenko

et al. 2018

Preprint

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“…To avoid the effect of neuronneuron interactions, if neurites touched neurites of other neurons, these neurons were excluded from the analysis. Neurites 50 µm or longer were defined as elongating neurites (Omura et al, 2015;Painter et al, 2014). At least 50 neurons were randomly selected per well, and the averages of the longest neurites and the percentage of neurons with elongating neurites were calculated.…”

Section: Neurite Outgrowth Assaymentioning

confidence: 99%

Evidence for cell‐contact factor involvement in neurite outgrowth of dorsal root ganglion neurons stimulated by Schwann cells

Endo

Kadoya

Kawamura

et al. 2019

Experimental Physiology

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New Findings What is the central question of this study?Although the factors secreted from Schwann cells that promote axonal growth in the peripheral nervous system have been well studied, the effect of cell‐contact factors on Schwann cells remains to be determined. What is the main finding and its importance?This study demonstrates that Schwann cells stimulate neurite outgrowth by direct contact with neurites and by secreting factors. Notably, the effect of cell‐contact factors in neurite outgrowth is comparable to that of secreted factors, indicating that the identification of cell surface molecules on Schwann cells that promote neurite outgrowth could lead to development of a new therapy for peripheral nervous system injury. Abstract Schwann cells (SCs) play a variety of roles in the regeneration process after injury to the peripheral nervous system. The factors secreted from SCs that promote axonal growth have been well studied. However, the involvement of cell‐contact factors on SCs remains to be determined. Here, we demonstrate a significant contribution of a cell‐contact mechanism in the effect of SCs on promotion of neuronal outgrowth. Neurite outgrowth of adult sensory neurons from dorsal root ganglia was quantified during co‐culture with adult SCs. Direct contact of SCs with neurons was eliminated by culturing SCs on an insert placed in the same well; this resulted in a 51% reduction in the length of neurite outgrowth. In addition, when dorsal root ganglion neurons were cultured on sparsely seeded SCs, neurons that made contact with SCs on their neurites had 118% longer neurites than neurons that lacked contacts with SCs. Collectively, these findings provide evidence that SCs stimulate neurite outgrowth via direct contact with neurites in addition to secreting factors. The identification of cell surface molecules on SCs that promote neurite outgrowth could lead to development of a new therapy for peripheral nervous system injury.

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“…Such studies provide one strategy toward identifying the molecular control elements of axon regeneration. To uncover additional regulatory genes, a comparison of inbred mouse strains that differ genetically in their regenerative capacity can reveal adaptive evolutionary strategies and the genes involved that favor peripheral or CNS regeneration (Omura et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

“…To understand the molecular changes promoting regeneration, we have taken advantage of two mouse strains C57BL/6 and CAST/Ei, that differ greatly in their regenerative capacity, as measured by regrowth of peripheral sensory neurons on inhibitory substrates both with and without a preconditioning injury (Omura et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Enhanced neuronal regeneration in the CAST/Ei mouse strain is linked to expression of differentiation markers after injury

Lisi

Singh

Giroux

et al. 2017

Preprint

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Peripheral nerve regeneration after injury requires a broad program of transcriptional changes. We investigated the basis for the enhanced nerve regenerative capacity of the CAST/Ei mouse strain relative to C57BL/6 mice. RNA sequencing of dorsal root ganglia (DRG) showed a CAST/Ei specific upregulation of Ascl1 after injury. Ascl1 overexpression in C57BL/6 mice DRG neurons enhanced their neurite outgrowth. Ascl1 is regulated by miR-7048-3p, which is down-regulated in CAST/Ei mice. Inhibition of miR-7048-3p enhances neurite outgrowth. Following injury, CAST/Ei neurons largely retained their mature neuronal profile as determined by single cell RNAseq, whereas the C57BL/6 neurons acquired an immature profile. These findings suggest that one facet of the enhanced regenerative phenotype is preservation of neuronal identity in response to injury.

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Robust Axonal Regeneration Occurs in the Injured CAST/Ei Mouse CNS

Cited by 15 publications

References 0 publications

Precise temporal regulation of alternative splicing during neural development

Precise temporal regulation of alternative splicing during neural development

Evidence for cell‐contact factor involvement in neurite outgrowth of dorsal root ganglion neurons stimulated by Schwann cells

Enhanced neuronal regeneration in the CAST/Ei mouse strain is linked to expression of differentiation markers after injury

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