In a study that could have significant consequences for neural tissue transplantation strategies, 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.
In a paper published in the Nov. 11 issue of PLoS Biology , the team, led by Fred H. Gage, Ph.D., professor in the Laboratory of Genetics, discovered that a protein called cdk5 is necessary for both correct elaboration of highly branched and complex antennae, known as dendrites, which are extended by neurons, and 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.
These findings offer extremely valuable, although unanticipated, input for investigators whose goal is to develop transplantation strategies to treat brain injuries or neurodegeneration.
"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.
Gage agrees that this is a possibility, noting that therapeutic targeting of new tissue—which would presumably be 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 part of the adult mouse brain known as the hippocampus, which is required 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 sported stunted, mistargeted dendrites.
Jessberger explains that one might have predicted the opposite: that if immature neurons in the adult brain accidentally oriented their antennae in the wrong direction, they might fail to connect with cells in that network, or possibly even die. That they formed synaptic contact points was highly unanticipated. "We found that dendrites of cells lacking cdk5 seemed to integrate into the brain no matter what direction they grew in," he says.