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Expression data from embryonic mouse cervical spinal cords

ABSTRACT: Mammalian motor circuits control voluntary movements by transmitting signals from the central nervous system (CNS) to muscle targets. To form these circuits, motor neurons (MNs) must extend their axons out of the CNS. Although motor axon exit from the CNS is an indispensable phase of motor axon pathfinding, the underlying molecular mechanisms remain obscure. Here, we present the first identification of a genetic pathway that regulates motor axon exit from the vertebrate spinal cord, utilizing spinal accessory motor neurons (SACMN) as a model system. SACMN are a homogeneous population of spinal MNs whose axons leave the CNS through a discrete lateral exit point (LEP) and can be visualized by the expression of the cell surface protein, BEN. We show that the homeodomain transcription factor, Nkx2.9, is selectively required for SACMN axon exit and identify the Robo2 guidance receptor as a likely downstream effector of Nkx2.9; loss of Nkx2.9 leads to a reduction in Robo2 mRNA and protein within SACMN and SACMN axons fail to exit the spinal cord in Robo2-deficient mice. Consistent with short-range interactions between Robo2 and Slit ligands regulating SACMN axon exit, Robo2-expressing SACMN axons normally navigate through LEP-associated Slits as they emerge from the spinal cord, and fail to exit in Slit-deficient mice. Our studies support the view that Nkx2.9 controls SACMN axon exit from the mammalian spinal cord by regulating Robo-Slit signaling.

ORGANISM(S): Mus musculus

PROVIDER: GSE47953 | GEO | 2013/06/15

SECONDARY ACCESSION(S): PRJNA208470

REPOSITORIES: GEO

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Expression data from embryonic mouse cervical spinal cords

Project description:Mammalian motor circuits control voluntary movements by transmitting signals from the central nervous system (CNS) to muscle targets. To form these circuits, motor neurons (MNs) must extend their axons out of the CNS. Although motor axon exit from the CNS is an indispensable phase of motor axon pathfinding, the underlying molecular mechanisms remain obscure. Here, we present the first identification of a genetic pathway that¬†regulates motor axon exit from the vertebrate spinal cord, utilizing spinal accessory motor neurons (SACMN) as a model system. SACMN are a homogeneous population of spinal MNs whose axons leave the CNS through a discrete lateral exit point (LEP) and can be visualized by the expression of the cell surface protein, BEN. We show that the homeodomain transcription factor, Nkx2.9, is selectively required for SACMN axon exit and identify the Robo2 guidance receptor as a likely downstream effector of Nkx2.9; loss of Nkx2.9 leads to a reduction in Robo2 mRNA and protein within SACMN and SACMN axons fail to exit the spinal cord in Robo2-deficient mice. Consistent with short-range interactions between Robo2 and Slit ligands regulating SACMN axon exit, Robo2-expressing SACMN axons normally navigate through LEP-associated Slits as they emerge from the spinal cord, and fail to exit in Slit-deficient mice. Our studies support the view that Nkx2.9 controls SACMN axon exit from the mammalian spinal cord by regulating Robo-Slit signaling. We utilized microarray technology to identify novel downstream effectors of the homeodomain transcription factor, Nkx2.9, that regulate spinal accessory motor neuron development.

2013-06-15 | E-GEOD-47953 | biostudies-arrayexpress

Developmental and Injury-induced Changes in DNA Methylation in Regenerative versus Non-regenerative Regions of the Vertebrate (Xenopus laevis) Central Nervous System Characterized by Whole Genome Bisulfite Sequencing (WGBS)

Project description:Xenopus is uniquely suited for identifying core features of successful CNS axon regeneration, because parts of its CNS (e.g., eye), regenerate axons throughout life, whereas others (e.g., hindbrain) do so only as tadpoles. We performed bisulfite whole genome bisulfite methylation sequencing (WGBS) on juvenile frog eye after optic nerve injury, and on hindbrain samples from tadpole and juvenile frog after spinal cord injury during the peak phase of axon regeneration, to compare tissue-related and injury-induced differences in DNA methylation among them.

2022-01-05 | GSE183355 | GEO

RNAseq of fluidically isolated human and mouse motor neuron somas and axons in vitro

Project description:Spinal motor axons traverse large distances to innervate target muscle, and thus require local control of cellular events for proper functioning of the distal axon. To interrogate axon-specific processes we developed Axon-seq, a refined method incorporating microfluidic devices and stringent bioinformatic quality controls. Axon-seq demonstrates improved sensitivity and accuracy in whole-transcriptome sequencing of axons compared to previously published studies. Importantly, we show that axon transcriptomes are distinct from those of somas, displaying fewer detected genes and no contaminating astrocytic markers. We identified >5,000 transcripts in stem cell-derived spinal motor axons required for local oxidative energy production and ribosome generation. Axons contained unique transcription factor mRNAs, e.g. Ybx1, with implications for local axonal functions. Cross-comparison with existing mouse motor axon datasets, as well as our own human motor axon data identified a common axon transcriptome. As motor axons degenerate in amyotrophic lateral sclerosis (ALS), we investigated their response to the disease-causing SOD1G93A mutation, identifying 121 ALS-dysregulated transcripts. Several of these are implicated in axonal and dendritic outgrowth, including Nrp1, Dbn1, and Nek1, a known ALS-causing gene. In conclusion, Axon-seq proves a robust and improved method for RNA-seq of axons, furthers our understanding of peripheral axon biology, and identifies novel therapeutic targets to maintain neural connectivity in disease.

2018-12-11 | GSE121069 | GEO

Identify a panel of transcripts that exhibited differential expression between spinal cord motor neurons (spMNs) with low and high regenerative abilities

Project description:The mammalian neurons in the central nervous system (CNS) fail to regenerate their axons after injury, while the adult peripheral nervous system (PNS) neurons can regenerate their axons robustly. Promoting the intrinsic regenerative capacity of CNS neurons after injury is potential way to solve this difficulty. For this purpose, we have identified a panel of transcripts that exhibited differential expression between spinal cord motor neurons (spMNs) with low and high regenerative abilities by using retrograde tracing and single-cell RNA sequencing.

2022-12-30 | GSE221115 | GEO

Identification of intrinsic growth modulators for intact CNS neurons after injury

Project description: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 circuits. 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.

2017-03-13 | GSE94482 | GEO

Activation of MAP2K signaling by genetic engineering or HF-rTMS promotes corticospinal axon sprouting and functional regeneration

Project description:B-RAF activation in mature corticospinal neurons upregulated a discrete set of transcription factors overlapping with a set induced early in axotomized zebrafish retina ganglion cells which can fully regenerate their axons. Conditional genetic activation of B-RAF promoted robust regeneration and sprouting of corticospinal tract axons after experimental spinal cord injury. Newly sprouting axon collaterals formed synaptic connections, correlating with recovery of skilled motor function. We also found that non-invasive suprathreshold high-frequency repetitive transcranial magnetic stimulation activates the RAF effector MEK and promotes regeneration and sprouting of corticospinal tract axons, dependent on MEK signaling. Our findings demonstrate a central role of neuron-intrinsic RAF–MEK signaling in enhancing the growth capacity of mature corticospinal neurons and propose transcranial magnetic stimulation as a potential therapy for spinal cord injury.

2022-12-31 | GSE201350 | GEO

Identification of molecular controls over corticospinal motor neuron segmental target specificity

Project description:Molecular mechanisms over differentiation and differential axonal targeting of distinct neuron subtypes in the cerebral cortex are beginning to be elucidated. These studies have focused on controls that specifically distinguish one subtype of neocortical projection neurons, e.g. corticospinal motor neurons (CSMN), from closely related corticothalamic projection neurons (CThPN) or intracortical callosal projection neurons (CPN). CSMN are located in layer V of the neocortex and make synaptic connections to motor output circuitry in the spinal cord and brainstem. CSMN axons form the corticospinal tract (CST), which is the major motor output pathway from the motor cortex and critically controls voluntary movement. CSMN somatotopically and precisely target specific segments along the rostrocaudal axis of the spinal cord, the molecular basis for which remains unknown. We used microarrays to examine gene expression differences between two CSMN subpopulations that target different levels of the spinal cord - CSMN-C (which extend axons to the brainstem and cervical spinal cord) and CSMN-L (which preferrrentially extend axons to the thoracic and lumbar spinal cord). We compared CSMN-C vs CSMN-L gene expression at 3 critical developmental time points (previously described in Arlotta et a., 2005)

2018-12-31 | GSE77311 | GEO

Comparative Gene Expression Profiling between Xenopus Optic Nerve and Spinal Cord Injury to Identify Genes Involved in Successful Regeneration of Vertebrate CNS Axons

Project description:Xenopus is uniquely suited for addressing the question of whether a core gene expression program for successful CNS axon regeneration exists, because parts of its CNS (e.g., eye), regenerate axons throughout life, whereas others (e.g., hindbrain) do so only as tadpoles. We performed RNA-Seq after optic nerve and spinal cord injury to identify trauma-induced genes shared between two regenerative CNS regions, but not shared with a non-regenerative one. We provide these data as a resource for new avenues of investigation into the molecular basis of tissue regeneration.

2020-08-07 | GSE137844 | GEO

Developmental and Injury-induced Changes in DNA Methylation in Regenerative versus Non-regenerative Regions of the Vertebrate (Xenopus laevis) Central Nervous System assayed by 5hmC MeDIP and by ChIP-seq for Histone Markers

Project description:Xenopus is uniquely suited for identifying core features of successful CNS axon regeneration, because parts of its CNS (e.g., eye), regenerate axons throughout life, whereas others (e.g., hindbrain) do so only as tadpoles. To aid in the interpretation of bisulfite whole genome methylation sequencing (WGBS) on juvenile frog eye after optic nerve injury, and on hindbrain samples from tadpole and juvenile frog after spinal cord injury during the peak phase of axon regeneration, we performed ChIP-seq for histone modifications associated with active gene expression (H3K4me3 & H3K27ac) and repressed gene expression (H3K27me3 & H3K9me3) on these same tissues, as well as DNA-immunoprecipitation sequencing (DIP seq) for 5-hydroxymethyl cytosine (5hmC) on eye samples during optic nerve regeneration.

2022-01-05 | GSE183350 | GEO

Location of Neonatal Microglia Drives Small Extracellular Vesicles Content and Biological Functions

Project description:Combining proteomics and systems biology analyses, we demonstrated that neonatal microglial cells derived from two different CNS locations (cortex and spinal cord) displayed different phenotypes upon different physiological or pathological conditions. These cells also exhibited great variability in terms of both cellular and small extracellular vesicles (sEVs) protein contents and levels. Bioinformatics data analysis showed that the cortical microglia had anti-inflammatory and neurogenesis/tumorigenesis properties, while the spinal cord microglia was rather involved in inflammatory response process. Of interest, while both sEVs microglia sources enhanced growth of DRGs axons, only the spinal cord-derived sEVs microglia under LPS stimulation significantly attenuated glioma proliferation. These results were confirmed through neurite outgrowth assays in DRGs cell line and glioma proliferation analysis in 3D spheroid cultures. Results from these in vitro assays indicated that the microglia localized at different CNS regions can ensure different biological functions. Together, these works indicate that neonatal microglia locations regulate their physiological and pathological functional fates, and could explain the high prevalence of brain vs. spinal cord glioma in adults.

2020-05-26 | PXD016093 | Pride

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