Network of differentially expressed genes after nerve injury. Nodes correspond to genes and edges to significant correlation: upregulation (red), downregulation (green) and transcription factors (yellow).
A UCLA-led collaboration has identified a specific network of genes and a pattern of gene-expression that promote repair in the peripheral nervous system in a mouse model. This network, the researchers found, doesn’t exist in the central nervous system. The researchers also found a drug that can promote nerve regeneration in the central nervous system.
“We know the transmission of messages (via nerve cells) can be impaired by injury, and the recovery of nerve cells after injury largely depends on their location,” said Vijayendran Chandran, PhD, a postdoctoral project scientist in the Department of Neurology. “Understanding these molecular differences in injured nerve cells in the limbs, where regeneration happens, versus injured nerve cells in the spinal cord, where regeneration fails, would open up the possibility to design treatment to enhance neuron regeneration in the central nervous system after injury.”
The researchers measured the response of gene regulation at the level of messenger RNA (mRNA) in each instance of injury. Gene regulation is the process of turning genes on and off, ensuring that genes are expressed at the right times. mRNA carries information from a gene that, in a long molecular cascade, ultimately tells a protein what to do. The researchers developed a unique set of algorithms to look at the interactions of various groups of genes and the order in which they were expressed.
“That allowed us to find common patterns that correlated with regeneration in the peripheral nervous system, and within those patterns, we were able to identify several genes not previously known that enhanced repair,” says Daniel Geschwind, MD (RES ’95, FEL ’97), Gordon and Virginia MacDonald Distinguished Chair in Human Genetics and professor of neurology and psychiatry and biobehavioral sciences. “But we did not find these patterns in the central nervous system. That was the major advance — identifying, in an unbiased way, 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.”
As a proof of principle that global patterns of gene expression could be used to screen for drugs that mimic the same pattern, the researchers used a publicly available database at UCLA's Broad Stem Cell Research Center to look for such a drug. That led them to one called Ambroxol, which significantly enhanced central nervous system repair.
“We’re excited about this study because there are a number of firsts that came out of it,” Dr. Geschwind says. “While we still have a long way to go from a mouse study to humans, we present a novel paradigm that has never been applied to the nervous system.”
“A Systems-level Analysis of the Peripheral Nerve Intrinsic Axonal Growth Program,” Neuron, March 2, 2016