The mammal’s nose is a work of evolutionary art. Its millions of nerve cells, each fitted with just one of the thousands of specific chemical odor receptors encoded in the genome, can collectively distinguish a trillion distinct odors. These senses, in turn, inform many behaviors, from evaluating food choices to distinguishing friends from foes to triggering memories.
Today, in the magazine NatureA research team led by scientists at Columbia’s Zuckerman Institute describes a previously undetected mechanism in mice – starring the genetic molecule RNA – that could explain how each sensory cell, or neuron, in the noses of mammals adapts to detect a specific chemical smell.
For example, there are sensory neurons in our nose that carry receptors uniquely tuned to detect ethyl vanillin, the main flavoring in vanilla, and other cells with receptors for limonene, the characteristic flavoring of lemon.
“How sensory cells in the nose make their receptor choices has been one of the most vexing mysteries about olfaction,” said Stavros Lombardas, PhD, Roy and Diana Vagelos Professor and Chair of Biochemistry and Molecular Biophysics and Herbert and Florence Irving Professor Neuroscience. at Columbia’s Zuckerman Institute and Vagelos College of Physicians and Surgeons, and corresponding author on the paper. “Now, the story behind our sense of smell, or sense of smell, is becoming clearer and also more dramatic.”
The sensory refinement drama to which he refers unfolds entirely within the microscopic confines of the nucleus of each olfactory neuron, where the cell’s chromosomes and genes reside. There, in a winner-takes-all Squid Games-style competition, a developing cell’s myriad olfactory receptor genes compete with each other in a process that gradually whittles them down, first to a handful of finalists and then to a single winner. The dominant gene is the one that determines the sensitivity of the cell to odors. In their study, Dr. Lombardas and his team reveal details of the final stage of this process, when the winner emerges from the finalist’s genes.
“It’s basically a battle between 1,000 candidates,” said Ariel Pourmorady, the paper’s first author and MD-Ph.D. candidate at the Zuckerman Institute in the Lomvardas lab.
The action is extremely complex and features a dizzying cast of molecular characters. Playing roles that either increase or decrease each gene’s ability to produce olfactory receptors are a variety of gene regulatory molecules. Assembling in various alliances within the genome, these molecular players help turn specific genes on or off.
Also in the fray is another set of molecular hubs that remodel parts of the genome in ways that favor specific receptor genes. When his team first noticed them in the genome in 2014, Dr. Lombardas called them “Greek Islands” because they reminded him of islands in the Aegean Sea.
“It turns out that the genome has a specific spatial organization in the nucleus, and changes in this structure are decisive when it comes to genes that are expressed in proteins, such as olfactory receptors,” Pourmorady said. “We are learning how important this process is in maturing olfactory cells.”
In their news Nature In the paper, the researchers bring together a wealth of data from mouse studies that point to RNA as the link molecule in the olfactory system’s gene selection machinery. RNA is best known as the intermediate molecule that translates the genetic code embedded in DNA into protein molecules with specific cellular tasks, such as detecting odors. But using sophisticated techniques to analyze changes in genome structure as cells mature, the researchers say their evidence points to a second pivotal role for RNA.
“It appears that the RNA that the cell makes during gene expression also changes the architecture of the genome in ways that boost expression of one olfactory receptor gene while also shutting down all others,” Pourmorady said.
Large gaps remain in this genome-control story, but researchers are telling the outline
becomes more defined. It begins with the maturation of olfactory cells, which initially express many receptor genes at those genomic nodes where gene-regulating molecules and complexes converge, including the Greek Islands.
The RNA then knocks the olfactory-receptor genes into one. The particular node in each cell where the molecular stars align to produce the highest amount of RNA wins the competition. In this center, receptor-gene expression soars. But, like a saboteur, RNA from the same node can reach all other nodes. At these sites, the RNA induces conformational changes in the genome that interrupt gene expression. The result is a nose of mature olfactory neurons, each bearing only one odorant receptor on its surface.
“We are reaching the edge of science fiction in terms of the molecular and genomic details we can now observe inside the nucleus of a single cell,” said Dr. Lombardas. “We have to keep coming back to figure out the rest of this olfactory puzzle.”