Nav: Home

Genes on the move help nose make sense of scents

January 09, 2019

NEW YORK -- The human nose can distinguish one trillion different scents -- an extraordinary feat that requires 10 million specialized nerve cells, or neurons, in the nose, and a family of more than 400 dedicated genes. But precisely how these genes and neurons work in concert to pick out a particular scent has long puzzled scientists. This is in large part because the gene activity inside each neuron -- where each of these 10 million neurons only chooses to activate one of these hundreds of dedicated genes -- seemed far too simple to account for the sheer number of scents that the nose must parse.

But now, a Columbia study in mice has uncovered a striking resourcefulness: by rearranging itself in three-dimensional space, the genome coordinates the regulation of these genes in each neuron, thereby generating the biological diversity needed to detect the scents we experience. The findings were published today in Nature.

"With today's study, we've pinpointed a genomic mechanism by which a finite number of genes can ultimately help distinguish a seemingly near-infinite number of scents," said Stavros Lomvardas, PhD, a principal investigator at Columbia's Mortimer B. Zuckerman Mind Brain Behavior Institute and the paper's senior author.

Smell, also known as olfaction, is mind-bogglingly complex. The receptors in our noses must not only identify a scent, but also gauge how strong it is, scan our memories to determine whether it has been encountered before, and determine if it is pleasing or toxic.

Olfactory receptor neurons, specialized nerve cells that snake from the nose to the brain, make all this possible. And though each neuron contains the full suite of the 400 dedicated olfactory receptor genes, only one of these genes is active in each neuron. Adding to the confusion: the gene that is active appears randomly chosen, and differs from neuron to neuron.

This unusual pattern of gene activity is known as the "one gene per neuron" rule, and has long been a focus of study by scientists such as Dr. Lomvardas. Indeed, deciphering how each olfactory receptor neuron manages to activate only one of these genes -- and how this process results in such a finely tuned sense of smell -- remained mysterious for decades.

"In mice, olfactory receptor genes are scattered across the genome at about 60 different locations -- on different chromosomes that are quite far apart from each other," said Kevin Monahan, PhD, a postdoctoral research scientist in the Lomvardas lab and the paper's co-first author. Mice have about 1,000 olfactory receptor genes, more than twice that of humans, potentially indicative of a superior sense of smell.

Traditionally, it has been thought that genes located on different chromosomes rarely, if ever, interacted with each other. By employing a new genomic sequencing technique called in situ Hi-C, Dr. Lomvardas and his team recently revealed that the chromosomes interacted much more frequently than expected.

"In situ Hi-C is revolutionary in large part because it allows us to map, in 3D, the entire genome inside a living cell," said Adan Horta, PhD, a recently graduated doctoral candidate in the Lomvardas lab and the paper's co-first author. "This gives us a snapshot of the genome at a particular point in time."

Snapshots taken by the researchers showed clusters of olfactory receptor genes, located on different chromosomes, physically moving toward each before choosing an olfactory receptor gene. Soon after these genes huddled together, another type of genetic element known as enhancers clustered in a separate 3D compartment. Enhancers are not themselves genes but regulate the activity of genes.

"We previously discovered a group of enhancers, we named the Greek Islands, located near the various olfactory receptor genes," said Dr. Horta. "This work showed that these enhancers create hotspots of activity to regulate the "chosen" olfactory receptor gene.

The team also found that the protein Ldb1 plays a key role in this process. It holds the Greek Islands together, allowing them to switch on a specific olfactory receptor gene that then -- as a team -- interpret the particular scent at hand.

"These teams of genes endow the olfactory system with the ability to respond in diverse ways," said Dr. Monahan. "The flexibility of this process could help to explain how we easily learn and remember new smells."

Though specific to olfaction, the researchers' findings could have implications for other areas of biology in which inter-chromosome interactions play a role.

"Interactions between chromosomes may be the culprit for shifts in the genome -- called genomic translocations -- that are known to cause cancer," said Dr. Lomvardas, who is also a member of the Kavli Institute for Brain Science at Columbia University as well as professor of biology and molecular biophysics and of neuroscience at Columbia University Irving Medical Center. "Could the activities of other cells be shaped by the three-dimensional changes we see in olfactory receptor neurons? This is an open question that we hope to explore."
-end-
This paper is titled "Lhx2/Ldb1-dependent multi-chromosomal compartments regulate singular olfactory receptor transcription."

This research was supported by the National Institutes of Health (F31 DC016785, F32 GM108474, U01DA0408052, R01DC013560, R01DC015451, S10OD020056)

The authors report no financial or other conflicts of interest.

Columbia University's Mortimer B. Zuckerman Mind Brain Behavior Institute brings together an extraordinary group of world-class scientists and scholars to pursue the most urgent and exciting challenge of our time: understanding the brain and mind. A deeper understanding of the brain promises to transform human health and society. From effective treatments for disorders like Alzheimer's, Parkinson's, depression and autism to advances in fields as fundamental as computer science, economics, law, the arts and social policy, the potential for humanity is staggering. To learn more, visit: zuckermaninstitute.columbia.edu.

The Zuckerman Institute at Columbia University

Related Neurons Articles:

How do we get so many different types of neurons in our brain?
SMU (Southern Methodist University) researchers have discovered another layer of complexity in gene expression, which could help explain how we're able to have so many billions of neurons in our brain.
These neurons affect how much you do, or don't, want to eat
University of Arizona researchers have identified a network of neurons that coordinate with other brain regions to influence eating behaviors.
Mood neurons mature during adolescence
Researchers have discovered a mysterious group of neurons in the amygdala -- a key center for emotional processing in the brain -- that stay in an immature, prenatal developmental state throughout childhood.
Astrocytes protect neurons from toxic buildup
Neurons off-load toxic by-products to astrocytes, which process and recycle them.
Connecting neurons in the brain
Leuven researchers uncover new mechanisms of brain development that determine when, where and how strongly distinct brain cells interconnect.
More Neurons News and Neurons Current Events

Best Science Podcasts 2019

We have hand picked the best science podcasts for 2019. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: TED Radio Hour

Erasing The Stigma
Many of us either cope with mental illness or know someone who does. But we still have a hard time talking about it. This hour, TED speakers explore ways to push past — and even erase — the stigma. Guests include musician and comedian Jordan Raskopoulos, neuroscientist and psychiatrist Thomas Insel, psychiatrist Dixon Chibanda, anxiety and depression researcher Olivia Remes, and entrepreneur Sangu Delle.
Now Playing: Science for the People

#537 Science Journalism, Hold the Hype
Everyone's seen a piece of science getting over-exaggerated in the media. Most people would be quick to blame journalists and big media for getting in wrong. In many cases, you'd be right. But there's other sources of hype in science journalism. and one of them can be found in the humble, and little-known press release. We're talking with Chris Chambers about doing science about science journalism, and where the hype creeps in. Related links: The association between exaggeration in health related science news and academic press releases: retrospective observational study Claims of causality in health news: a randomised trial This...