Insights into Cell Migration during Brain Development May Provide Clues into Cancer Cell Migration

A basic science lab studying cell mobility pathways in mammalian development at the Fred Hutchinson Cancer Research Center has elucidated a mechanism by which cells migrate within the developing mammalian brain that adds to the current knowledge on the way other cell types travel within the body: The research may be relevant to understanding how cancer cells metastasize.  

NOGO-A expression during cell migration. Source: Wikimedia Commons, Caltharp SA, Pira CU, Mishima N, et al. BMC Developmental Biology 2007 7:32 doi:10.1186/1471-213X-7-32

The paper, written by Jonathan Cooper, Ph.D., the director of the Hutchinson Center’s Basic Sciences Division and Yves Jossin, Ph.D., a post-doctoral fellow in the Cooper laboratory was published online April 24th in Nature Neuroscience (doi:10.1038/nn.2816). Jossin and Cooper set out to understand the role of specific factors in the cerebral cortex of the developing mouse brain. The cerebral cortex is the gray matter portion of the cerebrum and it plays a key role in memory, attention, thought, language, and consciousness. The cortex is made up of six layers of neurons, each with a specialized function, and all six layers are interconnected into circuits.

A key part of normal development, including in the brain, is the arrangement of cells into discrete tissues and organs. For this to occur, cells coordinate their migration and differentiation based on their position within the developing fetus, a process scientists still largely do not understand. In the cortex of the brain, cells develop by the sequential additions of neurons, and the inner layers develop first. New neurons move from the inside out, passing between already established neurons of the intermediate layers to form new outer layers. The mechanism of this orientation and migration was the subject of the newly published study. 

In this published paper, the researchers suggest the existance of a multi-step model whereby cortical neuron cells orient their migration within the intermediate zone of the cortex. Jossin and Cooper discovered novel signals that allow these cells to emerge from the intermediate zone of the cortex and begin to form new outer layers. They identified the signaling protein Reelin, previously implicated in influencing neurons within the intermediate zone, as having a key influence on new neurons as they emerge from the intermediate zone. 

“This is remarkable because the top layer of the cortex, where Reelin is made, is widely separated from the top of the intermediate zone, where it acts, so the Reelin protein must be diffuse,” Cooper said. “It is also remarkable that Reelin seems not to be a direction signal itself. Rather, Reelin triggers changes in the membranes of the migrating neurons that allow the cells to respond to direction signals,” he added.

The study also showed that when neurons encounter the protein Reelin, the amount of a cell membrane protein called N-cadherin increases on the surface of neurons. The polar distribution of N-cadherin on these cells allows them to choose the correcti direction of migration. “This represents a new and surprising function for N-cadherin,” Jossin said, “because normally this protein acts as a cellular stabilizer and not as an orchestrator of migration.” Indeed, N-cadherin normally forms tight seals between adjacent cells that prevent cell movement, and cadherins in general organize and stabilize cells into tissues. 

This novel function of N-cadherin is quite surprising and can now be investigated further in its roll in the migration of other cell types, including the mechanism of how tumor cells metastasize to other organs and tissues. “This finding could provide new clues to how normal and cancerous cells migrate within the body,” says Jossin.