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September 21, 2007

Layering and positioning neurons

Multipolar-to-biopolar neuronal transition is essential during brain development

Figure 1: Normal (left) and defective (right) dendritic development in mice lacking Cdk5. In mature neurons, neurites are referred to as either dendrites or axons.

© Development/The Company of Biologists/134/2279 (2007)

A team of Japanese scientists led by Toshio Ohshima, at the RIKEN Brain Science Institute, Wako, has determined that a protein called cyclin-dependent kinase 5 (Cdk5) is required for neurons to develop their proper shape. Morphological defects from a lack of Cdk5 affect the position and function of neurons in many parts of the brain, including the cerebral cortex—or gray matter.

Reporting in the June issue of Development1, Ohshima and colleagues extend their previous work that demonstrated proper migration of neurons to form the normal six layers of the cortex failed to occur in mice lacking Cdk5.

All cells of the body express Cdk proteins which are necessary for controlling when and how long cells divide. However, Cdk5 is different from other Cdk proteins in that it must be activated by specific ‘accessory’ proteins that are most highly expressed in neurons.

Ohshima and colleagues used several experimental approaches, including introducing a fluorescent ‘tag’ protein into developing brains to follow neuron migration in real-time, to evaluate the function of Cdk5.

As cortical neuron layers develop, the shape of neurons shifts from cells with multiple neuronal projections, or multipolar neurites, to cells with fewer neurites ‘pointing’ in opposite directions (‘bipolar’). The team found that in brains lacking Cdk5, however, the neurons remain multipolar.

This morphological defect was especially pronounced in so-called ‘pyramidal’ neurons (Fig. 1), which are specialized neurons with a single apical (‘top’) dendrite and many basal (‘bottom’) dendrites (hence their bipolar morphology) that represent nearly 80% of the neurons in the cortex.

Commenting on their work Ohshima says that he was initially intrigued with Cdk5 because it regulates proteins associated with devastating diseases such as Alzheimer’s and Amyotrophic Lateral Sclerosis. Serendipitously, however, the team found developmental defects in mice lacking Cdk5, which prompted further experiments.

The team’s new contribution adds to the well-accepted view that Cdk5 function is essential for normal brain development. Of particular note, the team found that pyramidal neurons require Cdk5 for multipolar-to-bipolar transition. But exactly which protein substrates Cdk5 regulates to bring about this transition is still not well understood.

“There are some candidates for Cdk5 substrates, but I have no direct evidence to say which one may be involved in its function,” says Ohshima. Indeed, the next step is to uncover the molecular pathway regulated by Cdk5. Using proteomics approaches—a combination of techniques to understand how proteins interact with one another—is one way Ohshima thinks he and his team can move forward.

References

  1. Ohshima, T., Hirasawa, M., Tabata, H., Mutoh, T., Adachi, T., Suzuki, H., Saruta, K., Iwasato, T., Itohara, S., Hashimoto, M. et al. Cdk5 is required for multipolar-to-bipolar transition during radial neuronal migration and proper dendrite development of pyramidal neurons in the cerebral cortex. Development 134, 2273–2282 (2007). |  | (Link)