Gene pathway responsible for peripheral nervous system regeneration identified.


It is known that the regenerative capacity of the injured central nervous system (CNS) in adult mammals is severely limited, yet axons in the peripheral nervous system (PNS) regrow, albeit to a limited extent, after injury.  Researchers hypothesize that differences in the regenerative potential between injured PNS neurons and injured CNS neurons reflect major differences in intrinsic transcriptional networks, however, these are yet to be mapped.  Now, a study from researchers led by UCLA has identified a specific network of genes that promote repair in the peripheral nervous system in a mouse model; importantly, this network doesn’t exist in the central nervous system. The team state that their findings also led them to identify a drug that promotes nerve regeneration in the central nervous system. The opensource study is published in the journal Neuron.

Previous studies support the concept that specific intrinsic molecular differences contribute to the divergent neuronal growth after PNS and CNS injuries.  This has been shown by the manipulation of individual candidate genes induced in neurons by PNS, but not CNS, injury, which can promote limited CNS regrowth after injury.

However, these findings also suggest that multiple pathways act in parallel to stimulate neuronal regeneration after injury.  The current study shows that the expression of transcription factors is coordinately upregulated following PNS injury, but not after CNS injury, consistent with the theory that coordinate regulation of this core network, rather than individual components, is necessary for axon regrowth.

The current study measured the response of gene regulation at the level of messenger RNA, or mRNA, in each instance of injury.  The lab state that they developed a unique set of algorithms to look at the interactions of various groups of genes and the order in which they were expressed.  Results identified common patterns that correlate with regeneration in the peripheral nervous system, and within those patterns the group were able to identify several genes not previously known that enhanced repair.  In contrast, data findings show that these patterns are not present in the central nervous system.

The team surmise that theirs is a major advance, identifying the entire network of pathways turned on in the peripheral nervous system when it regenerates, key aspects of which are missing in the central nervous system.  For the future, the researchers state that as a proof of principle that gene expression could be used to screen for drugs that mimic the same pattern, they identified the drug Ambroxol, which significantly enhanced central nervous system repair.

Source: UCLA
Targeting Candidate RAG Regulatory Network Using Small Molecules. Gene expression signatures after PNS injury were used to query drug-related expression profiles in the Connectivity Map. Using a pattern-matching algorithm, we selected three drugs (ambroxol, disulfiram, and lasalocid) based on enrichment and specificity scores. PPI (edges) network of co-expressed and differentially expressed genes (nodes) after PNS injury is shown. Upregulation (red) and downregulation (green) after SN lesion; upregulation (blue) and downregulation (purple) after ambroxol treatment (from Connectivity Map). A Systems-Level Analysis of the Peripheral Nerve Intrinsic Axonal Growth Program. Geschwind et al 2016.

Targeting Candidate RAG Regulatory Network Using Small Molecules. Gene expression signatures after PNS injury were used to query drug-related expression profiles in the Connectivity Map. Using a pattern-matching algorithm, we
selected three drugs (ambroxol, disulfiram, and lasalocid) based on enrichment and specificity scores.
PPI (edges) network of co-expressed and differentially expressed genes (nodes) after PNS injury is shown. Upregulation (red) and downregulation (green) after SN lesion; upregulation (blue) and downregulation (purple) after ambroxol treatment (from Connectivity Map). A Systems-Level Analysis of the Peripheral Nerve Intrinsic Axonal Growth Program. Geschwind et al 2016.

 

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