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Regeneration occurs in the CNS of CAST/Ei mice as a consequence of enhanced Activin signaling

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE55424 | GEO | 2015/05/14

SECONDARY ACCESSION(S): PRJNA239562

REPOSITORIES: GEO

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Regeneration occurs in the CNS of CAST/Ei mice as a consequence of enhanced Activin signaling

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

Robust axonal regeneration occurs in the injured CAST/Ei mouse central nervous system

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

Robust axonal regeneration occurs in the injured CAST/Ei mouse central nervous system

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Single cell sequencing of primary dorsal root ganglia from CAST/Ei or C57BL/6 mouse highlights strain differences in cellular populations.

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.

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A chemical genetic approach identifies piperazine antipsychotics as promoters of CNS neurite growth on inhibitory substrates.

Project description:Injury to the central nervous system (CNS) may result in lifelong loss of function due, in part, to the regenerative failure of CNS neurons. Major barriers to regeneration faced by injured CNS neurons include inhibitory proteins derived from myelin and the astroglial scar. Previously, we described the identification of a novel compound, F05, which promotes neurite growth from neurons challenged with inhibitory substrates in vitro, and promotes axonal regeneration in vivo (Usher et al., 2010). To identify additional regeneration promoting compounds, we used the microarray derived gene expression signature of F05 to query the Broad Institute Connectivity Map, a database of gene expression profiles for cells treated with >1,300 compounds. Unexpectedly, F05 induced changes in gene expression remarkably similar to those seen with a group of piperazine phenothiazine antipsychotics (PhAPs). We found that, in contrast to antipsychotics of other structural classes, PhAPs were able to promote neurite growth of CNS neurons cultured on two different glial-derived inhibitory substrates, but did not promote growth on a permissive substrate. Pharmacological studies suggest that the ability of PhAPs to promote growth depends on antagonism of calmodulin signaling, but not on dopamine receptor antagonism. Our findings shed light on mechanisms underlying neurite-inhibitory signaling, and suggest a potential pathway for development of novel treatments for CNS injury. 3 Biological Replicates of Vehicle Treated (0.05% DMSO) + 3 Biological Replicates of F05 Treated (5 μM)

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WT vs Hypomethylated DRG Gene Expression

Project description:Although DNA methylation plays a critical role in the development and function of mammalian central nervous system (CNS), its role in peripheral neurons has not been elucidated. To address this issue, we produced conditional knockout mice (CKO) specifically deleting the gene for maintenance DNA methyltransferase 1 (Dnmt1) during the development of neural crest cells. Despite global hypomethylation in the embryonic dorsal root ganglion (DRG) of the CKO mice, the number of sensory neurons was relatively unaffected. However, expression of many genes required for sensory neuron development was altered in embryonic mutant DRG, including down-regulation of Runx1 and TrkA genes as well as up-regulation of Id1 and Dtx1, two negative regulators for neurogenesis. Accompanied with the downregulation of an NGF receptor TrkA, the peripheral axonal projection and the branching of sensory neurons were impaired. Furthermore, the expression of the neuropeptide Galanin and several vanilloid receptors such as TrpV1 and TrpM8 were not detected in the DRG of the CKO mice during late embryonic and neonatal stages, suggesting that DNA methylation regulates the differentiation program for a subset of nociceptive sensory neurons. Taken together, our findings suggest that through transcriptional regulation of key developmental genes in sensory neurons, DNA methylation play a key role in the control of the axonal projection and fate specification of peripheral sensory neurons. We compared gene expression patterns in Wildtype and DNA methylation deficient (Wnt1-cre; Dnmt1 mutant) mouse dorsal cortex. We performed 4 replicates using different each individual mouse strain. The Sample GSM565172 table is the average log ratio for the 4 replicatesArrays were performed.

2011-12-01 | E-GEOD-23530 | biostudies-arrayexpress

A chemical genetic approach identifies piperazine antipsychotics as promoters of CNS neurite growth on inhibitory substrates.

2012-04-30 | GSE34331 | GEO

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