Neuron migration in the brain suggests how cancer cells might also travel

April 25, 2011

Abnormal neurons, in which the Reelin/N-cadherin pathway is blocked, are tracked in red (credit: Yves Jossin)

Researchers at Fred Hutchinson Cancer Research Center have found a new mechanism by which neurons migrate in the developing brain, suggesting how other types of cells, including cancer cells, may also travel within the body in metastasis.

New neurons initially move in a straight line, from the inside to the outside, until they reach a layer called the intermediate zone in the cortex. This zone contains relatively few neurons but many connecting fibers, or axons. When new neurons reach this layer, they lose their way and start wandering — up, down, left and right, frequently changing direction.

When, seemingly by chance, neurons emerge from the intermediate zone, they realign with their original direction of movement and speed ahead through layers of differentiated neurons towards the outer surface of the cortex.

The researchers aimed to determine how neurons get back on track after they emerge from the chaos of the intermediate zone. They identified a signaling protein, called Reelin, which is made by cells in the outermost layer of the cortex. It has been known that mutations in the Reelin gene cause profound cortical layering abnormalities in rodents and people, but it has been unclear which stage of neuron migration goes awry when Reelin is absent.

The researchers showed that new neurons respond to Reelin as they emerge from the intermediate zone. They also showed that a membrane protein called N-cadherin increases on the surface of neurons when the neurons encounter Reelin. The surface increase in N-cadherin allows the cell to choose the appropriate direction for its next stage of migration.

“The new role for N-cadherin in orienting migrating cells is quite unexpected and suggests that cadherins on the surface of other types of normal or cancer cells may also be involved in helping them move rather than stay in place,” the researchers suggest.

Tracking the life cycle of RNA molecules to detect cancer

In a related study, scientists at the Broad Institute have developed an approach that offers many windows into the life cycle of RNA molecules that will enable other scientists to investigate what happens when something in a cell goes wrong.

The scientists developed a method that allows them to tease apart the different stages of this life cycle by measuring how much messenger RNA (mRNA) is produced and how much is degraded. The balance of these two processes contributes to the changes seen in RNA levels in a cell over time, much the way that birth and death rates contribute to a country’s total population.

The scientists harnessed an existing technique to trace the fate of newly produced RNA and paired it with a new sequencing-based technology that counts molecules of mRNA. The results also gave the researchers a view of some of the in-between steps, during which mRNA is edited or processed — an unexpected but serendipitous finding.

The researchers were able to take “snapshots” of RNA levels over very short time intervals. Strung together, these snapshots reveal not only how the amount of RNA changes, but also the short-lived, intermediate phases of the RNA life cycle that are otherwise impossible to detect.

One critical application of the new method is in following up on leads from disease studies, such as mutated genes in cancer or other diseases that impact the RNA life cycle, the scientists said.

Ref.: Yves Jossin & Jonathan A Cooper, Reelin, Rap1 and N-cadherin orient the migration of multipolar neurons in the developing neocortex, April 24 online edition, Nature Neuroscience

Ref.: Ido Amit & Aviv Regev et al., Metabolic labeling of RNA uncovers principles of RNA production and degradation dynamics in mammalian cells, April 24 online edition, Nature Biotechnology