The histone-like H2BE protein (red) can be found in the nuclei
of olfactory neurons where it controls the expression of
odor-sensing receptors.

Image by Steve Santoro

Use It or Lose It

A protein helps tune nerves to the environment by killing off inactive cells in the nose.

For a newborn mouse pup, some smells are critical to survival: milk, mom, bedding. As the pup grows older, the critical smells change to predator, food source, and mate. Over time, a mouse’s olfactory system becomes more adept at detecting the odors that matter. HHMI investigator Catherine Dulac of Harvard University has uncovered a small molecule that plays a big role in this process.

Each odor-sensing nerve cell, or neuron, in a mammal’s nose is specialized to detect a single type of smell. Because a typical mammal has about 1,000 odorant receptors, a fraction of which are needed at any one time, Dulac hypothesized that an animal might be able to “tune” its olfactory system to the environment by choosing which receptor to express at a given time.

Dulac and research associate Stephen Santoro found that olfactory neurons containing a protein called H2BE die sooner than neurons without the protein. H2BE is closely related to H2B, a histone, which helps organize DNA into compact forms that can fit inside a cell’s nucleus and participates in regulating gene expression. Furthermore, as the team reported in the journal eLife on December 13, 2012, H2BE levels are inversely related to how active a cell is. Neurons with receptors that are constantly stimulated by smells have lower H2BE levels and thus live longer.

This animation shows how DNA is tightly packed to fit into a cell’s nucleus.

H2BE, they discovered, was replacing H2B in inactive neurons. “Slowly but surely, the genomes of neurons that are not very active become populated by H2BE instead of H2B,” Dulac explains. The presence of H2BE instead of H2B causes DNA transcription to change dramatically and to slow down, and the cell eventually dies.

This system provides a novel mechanism by which an animal adapts its selection of nasal neurons to the environment. When the animal is constantly surrounded by certain smells, the receptors corresponding to the various odorants are stimulated and the neurons expressing those receptors live longer. Neurons for rarely occurring smells—for example, mother’s milk once a pup matures—have a limited lifespan.

There are still many uncharacterized histone-like molecules in the brain, and Dulac believes that this novel system of regulation may be applicable to other brain functions.