How the brain forms

Wednesday, February 17, 2016

The human brain can process a picture in just 13 milliseconds. The cellular functions underlying this incredible processing speed involve not just neurons, but also a supporting cast of other types of brain cells. Among these, oligodendrocytes are one of the key players.

Oligodendrocytes support neuronal firing by wrapping the axons in a protein known as myelin, creating an insulating sheath that speeds up the rate of firing. The importance of myelination is underscored by diseases where it is disrupted — in particular multiple sclerosis (MS) — that leads to an array of symptoms including sensory and movement problems.

During development, oligodendrocyte precursor cells (OPCs) develop in a particular zone and migrate out to cover and myelinate the central nervous system. However, until recently, it was unclear exactly what guides OPCs used to migrate.

A recent report in Science from the Fancy lab begins to answer this fundamental question of development.

The authors began by observing where OPCs were located in developing mouse and human brains. They found that these cells were strongly associated with brain blood vessels. In fact, 58% of OPCs had their cell bodies directly associated with blood vessels. Of the remaining third, 67% had at least one process, or cell extension, that touched a vessel.

To more closely observe the behavior of OPCs during development, the authors took slices of developing mouse brains where OPCs were labeled by a fluorescent marker.

They observed two key behaviors. The cells either crawled along blood vessels, or jumped from one blood vessel to another. In order to jump, an OPC extends a process from one blood vessel to another, and then the cell body follows the process to the new blood vessel.

In order to determine whether the presence of blood vessels was necessary for OPC migration, the authors took advantage of mouse models where a deletion of a specific gene disrupts vessel development.

When vessels were disrupted, OPCs failed to populate the surrounding grey matter. OPC death was not increased, suggesting that this failure was due specifically to migration defects.

Next, the paper addressed what cellular signals cause OPCs to associate with blood vessels.

The authors hypothesized that once OPC migration stopped, they begin to differentiate into oligodendrocytes. Wnt signaling is an important cellular pathway that inhibits OPC differentiation, and therefore possibly promotes OPC association with vessels and migration.

To test this hypothesis, the authors used a mouse model where Wnt signaling is always on. This constant Wnt signaling led to a higher number of OPCs associated with vessels, and fewer differentiated OPCs. In a complementary experiment, inhibition of Wnt signaling in brain slices led to reduced OPC-vessel association and decreased migration.

This work underscores the importance of blood vessel association and Wnt signaling in the migration of OPCs and the development of a mature brain.

These same developmental mechanisms may also occur during injury or diseases, providing potential mechanisms for speeding up the healing process or combating diseases like MS, and maintaining the powerful firing speed of the human brain.