A new study published in this week's PLoS Biology could have significant consequences for neural tissue transplantation to treat brain injuries or neural degeneration. Researchers at the Salk Institute for Biological Studies report that inactivating a specific gene in adult neural stem cells makes nerve cells emerging from those precursors form connections in the wrong part of the adult brain.
The research team, led by Professor Fred H. Gage, Ph.D., discovered that a protein called cdk5 is necessary for both correct elaboration of highly branched and complex dendrites, a kind of antennae which are extended by neurons. Cdk5 is also involved in the proper migration of cells bearing those antennae.
Previously described functions of cdk5 are manifold, among them neuronal migration and dendritic pathfinding of neurons born during embryonic development. "The surprising element was that the dendrites of newborn granule cells in the adult hippocampus lacking cdk5 stretched in the wrong direction and actually formed synapses with the wrong cells," explains Gage. Synapses are the specialized contact points where dendrites receive input from the long processes, or axons, of neighboring neurons. The investigators injected retroviruses into the hippocampus of adult mice to tag and knock out cdk5 activity in newborn granule cell neurons.
These findings offer extremely valuable, unanticipated insight, "Our data shows that cells that fail to find their 'right spot' might actually become integrated into the brain and possibly interfere with normal information processing," says the study's lead author Sebastian Jessberger, M.D., a former postdoc in the Gage lab and now an assistant professor at the Swiss Federal Institute of Technology in Zurich, Switzerland. "We found that dendrites of cells lacking cdk5 seemed to integrate into the brain no matter what direction they grew in," he says.
Gage notes that the findings, "reflect the need for therapeutic approaches that will assure that cells used in regenerative medicine are strategically placed so that they will make appropriate rather than promiscuous connections."
In fact, the inappropriate synaptic connections made by cdk5-deficient cells persisted for months after the treatment with cdk5-antagonizing retroviruses. "One might have predicted that aberrant maturing nerve cells would get kicked out of the circuitry later on," reports Jessberger, who followed the behavior of newborn granule cells in treated mice long after cdk5 activity was eliminated. "Even after one year, some of those cells remained in the wrong part of the hippocampus."
"The nice part of this story is that it emerged from a systems genetics approach we used in a previous study," says Gage. "It continues our effort to apply genetic analysis to find chromosomal regions harboring genes that may play a critical role in neurogenesis."
Citation: Jessberger S, Aigner S, Clemenson GD Jr, Toni N, Lie DC, et al. (2008) Cdk5 regulates accurate maturation of newborn granule cells in the adult hippocampus. PLoS Biol 6(11): e272. doi:10.1371/journal.pbio.0060272
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Department of Biology
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