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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE34331 | GEO | 2012/04/30

SECONDARY ACCESSION(S): PRJNA151493

REPOSITORIES: GEO

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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)

2012-04-29 | E-GEOD-34331 | biostudies-arrayexpress

Homo sapiens

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

| PRJNA151493 | ENA

Erinacine S from Hericium erinaceus Mycelium Promotes Neuronal Regeneration by Inducing Neurosteroids Accumulation

Project description:To study the underlying mechanism of erinacines derived from Hericium erinaceus in neuroprotective effect against neurodegenerative diseases, we used the next-generation sequencing technology and bioinformatic analyses, erinacine S was found to cause the accumulation of neurosteroids in neurons. Additionally, we found that erinacine S enhances neurite outgrowth in a cell autonomous fashion of primary neurons. It also promotes post-injury axon regeneration of PNS neurons and enhances regeneration on inhibitory substrates of CNS neurons. This research uncovers a previously unknown effect of erinacine S on promoting neuronal regeneration via raising the level of neurosteroids.

2023-05-31 | GSE208121 | GEO

Phenotypic Screening Following Transcriptomic Deconvolution to Identify Transcription Factors Mediating Axon Growth Induced by a Kinase Inhibitor

Project description:After injury to the central nervous system (CNS), both neuron-intrinsic limitations on regenerative responses and inhibitory factors in the injured CNS environment restrict regenerative axon growth. Instances of successful axon regrowth offer opportunities to identify features that differentiate these situations from that of the normal adult CNS. One such opportunity is provided by the kinase inhibitor RO48, which dramatically enhances neurite outgrowth of neurons in vitro and substantially increased contralateral sprouting of corticospinal tract neurons when infused intraventricularly following unilateral pyramidotomy. The authors present here a transcriptomic deconvolution of RO48-associated axon growth, with the goal of identifying transcriptional regulators associated with axon growth in the CNS. Through the use of RNA sequencing (RNA-seq) and transcription factor binding site enrichment analysis, the authors identified a list of transcription factors putatively driving differential gene expression during RO48-induced neurite outgrowth of rat hippocampal neurons in vitro. The 82 transcription factor motifs identified in this way included some with known association to axon growth regulation, such as Jun, Klf4, Myc, Atf4, Stat3, and Nfatc2, and many with no known association to axon growth. A phenotypic loss-of-function screen was carried out to evaluate these transcription factors for their roles in neurite outgrowth; this screen identified several potential outgrowth regulators. Subsequent validation suggests that the Forkhead box (Fox) family transcription factor Foxp2 restricts neurite outgrowth, while FoxO subfamily members Foxo1 and Foxo3a promote neurite outgrowth. The authors’ combined transcriptomic-phenotypic screening strategy therefore allowed identification of novel transcriptional regulators of neurite outgrowth downstream of a multitarget kinase inhibitor.

2023-06-19 | GSE234696 | GEO

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

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

2015-05-14 | GSE55424 | GEO

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

Soluble SORLA enhances neurite outgrowth and regeneration through activation of EGFR and MAPK pathways

Project description:SORLA is a type I transmembrane component associated with Alzheimers disease (AD) risk. Although SORLA is abundantly expressed in neurons, physiological roles for SORLA remain yet unclear. Here, we show that cultured neurons overexpressing SORLA (SORLA TG) feature enhanced neurite length, and accelerated neurite regeneration with wounding. Enhanced accumulation of a soluble SORLA form (sSORLA) is observed in SORLA TG neurons, where purified sSORLA can sufficiently drive neurite extension and regeneration. Phosphoproteomic analysis indicates enrichment of phosphoproteins related to the EGFR/ERK pathway in SORLA TG hippocampus. We find that sSORLA can co-precipitate with EGFR in vitro, where sSORLA treatment can induce EGFR Y1173 phosphorylation in cultured neurons. sSORLA also triggers Erk activation and downstream c-fos upregulation/nuclear translocation, where pharmacological EGFR or ERK inhibition reversed enhancements in sSORLA-dependent neurite regeneration. Together, these results implicate the EGFR as a sSORLA receptor which activates ERK/c-Fos pathways to enhance neurite extension, outgrowth and regeneration.

2020-05-12 | MSV000085400 | MassIVE

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

2015-07-22 | GSE67130 | GEO

Jun promotes axon regeneration by binding enhancer sites and dimerizing with Atf3

Project description:Axon regeneration is a necessary step toward functional recovery after spinal cord injury. The AP-1 transcription factor c-Jun has long been known to play an important role in directing the transcriptional response of Dorsal Root Ganglion (DRG) neurons to peripheral axotomy that results in successful axon regeneration. Here we performed ChIPseq for Jun in mouse DRG neurons after a sciatic nerve crush or sham surgery in order to measure the changes in Jun’s DNA binding in response to peripheral axotomy. We found that the majority of Jun’s injury-responsive changes in DNA binding occur at putative enhancer elements, rather than proximal to transcription start sites. We also used a series of single polypeptide chain tandem transcription factors to test the effects of different Jun-containing dimers on neurite outgrowth in cortical and hippocampal neurons. These experiments demonstrated that dimers composed of Jun and Atf3 promoted neurite outgrowth in rat CNS neurons. Our work provides new insight into the mechanisms underlying Jun’s role in axon regeneration.

2018-08-06 | GSE105442 | GEO

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