Transcriptional regulation of gene expression clusters in motor neurons following spinal cord injury

Abstract

BackgroundSpinal cord injury leads to neurological dysfunctions affecting the motor, sensory as well as the autonomic systems. Increased excitability of motor neurons has been implicated in injury-induced spasticity, where the reappearance of self-sustained plateau potentials in the absence of modulatory inputs from the brain correlates with the development of spasticity.ResultsHere we examine the dynamic transcriptional response of motor neurons to spinal cord injury as it evolves over time to unravel common gene expression patterns and their underlying regulatory mechanisms. For this we use a rat-tail-model with complete spinal cord transection causing injury-induced spasticity, where gene expression profiles are obtained from labeled motor neurons extracted with laser microdissection 0, 2, 7, 21 and 60 days post injury. Consensus clustering identifies 12 gene clusters with distinct time expression profiles. Analysis of these gene clusters identifies early immunological/inflammatory and late developmental responses as well as a regulation of genes relating to neuron excitability that support the development of motor neuron hyper-excitability and the reappearance of plateau potentials in the late phase of the injury response. Transcription factor motif analysis identifies differentially expressed transcription factors involved in the regulation of each gene cluster, shaping the expression of the identified biological processes and their associated genes underlying the changes in motor neuron excitability.ConclusionsThis analysis provides important clues to the underlying mechanisms of transcriptional regulation responsible for the increased excitability observed in motor neurons in the late chronic phase of spinal cord injury suggesting alternative targets for treatment of spinal cord injury. Several transcription factors were identified as potential regulators of gene clusters containing elements related to motor neuron hyper-excitability, the manipulation of which potentially could be used to alter the transcriptional response to prevent the motor neurons from entering a state of hyper-excitability.

RETRACTED ARTICLE: Analyzing time-series microarray data reveals key genes in spinal cord injury

“…Recently, many scholars have utilized high-throughput microarrays to delineate gene expression patterns after SCI [9][10][11][12][13]. However, no study has evaluated the gene expression changes in raphe magnus (RM) and somatomotor cortex (SMTC), two areas in brain primarily affected by SCI.…”

A Systems-Level Analysis of the Peripheral Nerve Intrinsic Axonal Growth Program

“…To test this, we examined the gene expression levels of these over-represented TFs in independent published PNS and CNS spinal cord injury profiling data (Di Giovanni et al, 2003; Ryge et al, 2010; Table S4). Regardless of the model, these TFs were significantly co-expressed and upregulated after PNS injury (Figure 4E; Figure S2).…”

Spinal circuits for motor learning

“…Instructive (proprioceptive) input is crucial for the development of normal spinal locomotor circuit function [63 ]. Following spinal cord injury, there are many changes to spinal motor circuits [6] including in MN gene expression such as chloride transporters [64,65], ligand and voltage-gated channels [65], or serotonin receptors [66]. While these responses may be homeostatic changes in response to loss of input, these changes can lead to increased excitability resulting in spasticity [67 ,68 ].…”