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Neural stem cells deficient in specific protein cause improper brain cell development

Posted Nov 11 2008 2:26pm

Inactivating a specific gene in adult neural stem cells makes emerging nerve cells form inaccurate connections in the brain, according to a study published in today’s PLoS Biology 

The investigators believe the finding could have significant value for researchers working on neural tissue regeneration to treat brain injuries and neurological diseases. Fred H. Gage, PhD, professor in the Laboratory of Genetics at theSalk Institute in La Jolla, Calif., and colleagues found thatthe cdk5 protein is necessary for both correct development of dendrites (which can be compared to   many branched and complex antennae), their neuron extensions, and the proper migration of cells bearing those antennae.  

  “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,” according to Gage. Synapses are the contact points where dendrites receive input from the long processes, or axons, of neighboring neurons.   

“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,” said study author Sebastian Jessberger, MD, a former postdoc in Gage’s lab and now an assistant professor at the Swiss Federal Institute of Technology in Zurich, Switzerland. 

Gage noted that the therapeutic targeting of new tissue, presumably derived from stem cells, to the brain or spinal cord may demand extreme accuracy. “Our 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 the study investigators first injected retroviruses into the adult mouse brain hippocampus (responsible for memory formation) to tag and knock out cdk5 activity in newborn granule cell neurons. Over time they observed that newborn neurons not only failed to move to their correct position in the brain but also developed mistargeted dendrites. 

“We found that dendrites of cells lacking cdk5 seemed to integrate into the brain no matter what direction they grew in,” Jessberger said. “That they formed synaptic contact points was highly unanticipated. 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. Even after one year, some of those cells remained in the wrong part of the hippocampus.” 

The study builds on previous work in which the Gage lab searched the whole genome for chromosomal hot spots associated with adult neurogenesis, and specifically a 2005 PNAS study that identified a large region of mouse chromosome 5 as an area of interest, and cdk5 was a gene embedded within that locus.

“The nice part of this story is that it emerged from a systems genetics approach,” says Gage. “It continues our effort to apply genetic analysis to find chromosomal regions harboring genes that may play a critical role in neurogenesis.” 
 

The study was supported by the Swiss National Science Foundation and the Deutsche Forschungsgemeinschaft and grants from the National Institutes of Health, the Lookout Fund, the Christopher and Dana Reeve Foundation, the Picower Foundation, the James S. McDonnell Foundation, and the Damon Runyon Cancer Research Foundation.  

Citation:  

Cdk5 Regulates Accurate Maturation of Newborn Granule Cells in the Adult HippocampusJessberger S, Aigner S, Clemenson Jr. GD, Toni N, Lie DC, et al. PLoS BiologyVol. 6, No. 11, e272 doi:10.1371/journal.pbio.0060272

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