Enhanced neuronal regeneration in the CAST/Ei mouse strain is linked to expression of differentiation markers after injury
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE98417 | GEO | 2017/08/01
SECONDARY ACCESSION(S): PRJNA385020
REPOSITORIES: GEO
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Project description: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 DRG neurons of C57BL/6 mice enhanced their neurite outgrowth. Ascl1 is regulated by miR-7048-3p, which is downregulated 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 RNA- seq, 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.
| S-EPMC5565222 | biostudies-literature
Project description:Enhanced neuronal regeneration in the CAST/Ei mouse strain is linked to expression of differentiation markers after injury
| PRJNA385020 | ENA
Project description:Axon regeneration in the CNS requires reactivating injured neurons' intrinsic growth state and enabling growth in an inhibitory environment. Using an inbred mouse neuronal phenotypic screen, we find that CAST/Ei mouse adult dorsal root ganglion neurons extend axons more on CNS myelin than the other eight strains tested, especially when pre-injured. Injury-primed CAST/Ei neurons also regenerate markedly in the spinal cord and optic nerve more than those from C57BL/6 mice and show greater sprouting following ischemic stroke. Heritability estimates indicate that extended growth in CAST/Ei neurons on myelin is genetically determined, and two whole-genome expression screens yield the Activin transcript Inhba as most correlated with this ability. Inhibition of Activin signaling in CAST/Ei mice diminishes their CNS regenerative capacity, whereas its activation in C57BL/6 animals boosts regeneration. This screen demonstrates that mammalian CNS regeneration can occur and reveals a molecular pathway that contributes to this ability.
| S-EPMC4458182 | biostudies-literature
Project description:We screened nine genetically diverse inbred mouse strains for differences in axonal growth of adult dorsal root ganglion (DRG) neurons on CNS myelin. Naïve DRG neurite outgrowth on myelin was very limited, but preconditioning the neurons by a prior sciatic nerve crush increased axonal growth substantially across all strains, with by far the greatest change in neurons from CAST/Ei mice. Three independent in vivo CNS injury models revealed greater capacity for CNS axonal regeneration in CAST/Ei than C57BL/6 mice. Full-genome expression profiling of naïve and pre-conditioned DRGs across all strains revealed Activin-βA (Inhba) as the transcript whose expression most closely correlated with axonal growth on myelin. In vitro and in vivo gain- and loss-of-function experiments confirmed that Activin promotes axonal growth in the CNS. Substantial regeneration is possible, therefore, in the injured mammalian CNS when Activin signaling is intrinsically high, as in CAST/Ei or when extrinsically modulated in other strains.
2015-05-14 | GSE55424 | GEO
Project description:We screened nine genetically diverse inbred mouse strains for differences in axonal growth of adult dorsal root ganglion (DRG) neurons on CNS myelin. Naïve DRG neurite outgrowth on myelin was very limited, but preconditioning the neurons by a prior sciatic nerve crush increased axonal growth substantially across all strains, with by far the greatest change in neurons from CAST/Ei mice. Three independent in vivo CNS injury models revealed greater capacity for CNS axonal regeneration in CAST/Ei than C57BL/6 mice. Full-genome expression profiling of naïve and pre-conditioned DRGs across all strains revealed Activin-βA (Inhba) as the transcript whose expression most closely correlated with axonal growth on myelin. In vitro and in vivo gain- and loss-of-function experiments confirmed that Activin promotes axonal growth in the CNS. Substantial regeneration is possible, therefore, in the injured mammalian CNS when Activin signaling is intrinsically high, as in CAST/Ei or when extrinsically modulated in other strains. 9 strains, 4 replicates per strain, 2 conditions (naïve and axotomy) = 72 samples. 2 samples were excluded because technical outliers (AJ_AX5D_1 and AJ_NAIVE_4 excluded from the normalized data but included in the raw data)
2015-05-14 | E-GEOD-55424 | biostudies-arrayexpress
Project description:Axon regeneration in the central nervous system (CNS) requires reactivating injured neurons’ intrinsic growth state and enabling growth in an inhibitory environment. Using an inbred mouse neuronal phenotypic screen, we find that CAST/Ei mouse adult dorsal root ganglion neurons extend axons more on CNS myelin than the other eight strains tested, especially when pre-injured. Injury-primed CAST/Ei neurons also regenerate markedly in the spinal cord and optic nerve more than those from C57BL/6 mice and show greater spouting following ischemic stroke. Heritability estimates indicate that extended growth in CAST/Ei neurons on myelin is genetically determined, and two whole-genome expression screens yield the Activin transcript Inhba as most correlated with this ability. These screens are presented here.
2015-07-22 | GSE67130 | GEO
Project description:Axon regeneration in the central nervous system (CNS) requires reactivating injured neurons’ intrinsic growth state and enabling growth in an inhibitory environment. Using an inbred mouse neuronal phenotypic screen, we find that CAST/Ei mouse adult dorsal root ganglion neurons extend axons more on CNS myelin than the other eight strains tested, especially when pre-injured. Injury-primed CAST/Ei neurons also regenerate markedly in the spinal cord and optic nerve more than those from C57BL/6 mice and show greater spouting following ischemic stroke. Heritability estimates indicate that extended growth in CAST/Ei neurons on myelin is genetically determined, and two whole-genome expression screens yield the Activin transcript Inhba as most correlated with this ability. These screens are presented here. Biological quadruplicate - Mouse tissue - Naïve Dorsal Root Ganglia (DRG) and 5 day post sciatic nerve crush DRG - x9 strains.
2015-07-22 | E-GEOD-67130 | biostudies-arrayexpress
Project description:Peripheral nerve regeneration after injury is a complex process involving a large number of transcriptional changes. How these changes impact the regenerative outcome is though, poorly understood. Here, we take advantage of the genetically based differences in the peripheral and central regenerative capacity of CAST/Ei and C57BL/6j inbred mice to better understand the molecular bases driving superior regeneration in the CAST/Ei mouse strain. Single cell RNA sequencing highlighted the existence of three populations of cells, one of which expressed genes enriched for mature neuronal function, another one had a gene expression profile enriched for an immature dedifferentiated state while the third one showed an intermediate profile between these two extremes. The immature expression state was observed after injury in both strains but a larger proportion of the CAST/Ei neurons retained an expression pattern consistent with neuronal identity whereas a larger proportion of C57BL/6 neurons acquired an immature gene expression state accompanied by expression of stress markers. This finding suggests that unexpectedly, maintenance of a mature differentiated state in injured neurons increased regenerative success.
2017-08-01 | GSE98415 | GEO
Project description:Classical inbred mice are extensively used for virus research. However, we recently found that some wild-derived inbred mouse strains are more susceptible than classical strains to monkeypox virus. Experiments described here indicated that the 50% lethal dose of vaccinia virus (VACV) and cowpox virus (CPXV) were two logs lower in wild-derived inbred CAST/Ei mice than classical inbred BALB/c mice, whereas there was little difference in the susceptibility of the mouse strains to herpes simplex virus. Live bioluminescence imaging was used to follow spread of pathogenic and attenuated VACV strains and CPXV virus from nasal passages to organs in the chest and abdomen of CAST/Ei mice. Luminescence increased first in the head and then simultaneously in the chest and abdomen in a dose-dependent manner. The spreading kinetics was more rapid with VACV than CPXV although the peak photon flux was similar. These data suggest advantages of CAST/Ei mice for orthopoxvirus studies.
| S-EPMC3902144 | biostudies-literature
Project description:Neural stem cells in the subventricular zone (SVZ) of the adult mammalian forebrain are a potential source of neurons for neural tissue repair after brain insults such as ischemic stroke and traumatic brain injury (TBI). Recent studies show that neurogenesis in the ventricular zone (VZ) of the adult zebrafish telencephalon has features in common with neurogenesis in the adult mammalian SVZ. Here, we established a zebrafish model to study injury-induced neurogenesis in the adult brain. We show that the adult zebrafish brain possesses a remarkable capacity for neuronal regeneration. Telencephalon injury prompted the proliferation of neuronal precursor cells (NPCs) in the VZ of the injured hemisphere, compared with in the contralateral hemisphere. The distribution of NPCs, viewed by BrdU labeling and ngn1-promoter-driven GFP, suggested that they migrated laterally and reached the injury site via the subpallium and pallium. The number of NPCs reaching the injury site significantly decreased when the fish were treated with an inhibitor of ?-secretase, a component of the Notch signaling pathway, suggesting that injury-induced neurogenesis mechanisms are at least partly conserved between fish and mammals. The injury-induced NPCs differentiated into mature neurons in the regions surrounding the injury site within a week after the injury. Most of these cells expressed T-box brain protein (Tbr1), suggesting they had adopted the normal neuronal fate in this region. These results suggest that the telencephalic VZ contributes to neural tissue recovery following telencephalic injury in the adult zebrafish, and that the adult zebrafish is a useful model for regenerative medicine.
| S-EPMC3291641 | biostudies-literature