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Puberty and Sense of Smell: What Do They Have in Common?

Puberty and Sense of Smell: What Do They Have in Common? content piece image
The image contains a circular structure within the developing nose that gives rise to puberty-inducing neurons (green). Some of these neurons leave their birth place to travel along nerve cables. These cells and the cables also have the PLXNA3 molecule, which is colored red, but appears yellow, because of the red and green overlap. All cells are also highlighted in blue. Credit: Roberto Oleari, University of Milan
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Researchers have identified a group of genes that are involved in the development of the sense of smell and onset of puberty in mice. Published in Development, these findings could improve our understanding of puberty and the signs and symptoms of Kallmann syndrome (KS).

What is Kallmann syndrome?

KS is an inherited genetic disorder, characterized by the delay or complete absence of pubertal onset, leading to underdeveloped genitalia, depleted sex drive and lack of the growth spurt commonly associated with puberty. This is thought to be caused by the absence or misplacement of gonadotropin-releasing hormone (GnRH) neurons.

However, there is one particular feature of KS that makes it unique amongst other reproductive conditions – patients with KS have no sense of smell. But how does this link to the onset of puberty?

Common origins

In the new study, researchers identified two genes, PLXNA1 and PLXNA3, that were expressed in the neurons that extend from the nose into the brain of developing mice.2

"By studying the mouse as a model organism, we have identified a pair of genes that can cause an inherited condition with symptoms similar to human KS. This is an important finding, because the nerves that convey our sense of smell and that guide the puberty-inducing nerve cells arise in a very similar way during the development of mice and humans whilst they are still in the womb," explained Professor Christiana Ruhrberg, leader of the UK team.

The neurons Rurhberg refers to not only transmit signals necessary for sense of smell, but also guide hormone-secreting neurons, such as those secreting GnRH, from their nasal origin to the hypothalamus. From here, the hypothalamic-pituitary axis regulates the onset of puberty under normal physiological conditions.

When the researchers knocked out the genes PLXNA1 and PLXNA3 in mice, they found that both types of neuron were affected. The areas responsible for processing smells were abnormal, and the GnRH-secreting neurons were absent. Both are features seen in patients with KS.

A new genetic test on the horizon?

With further research, the link between PLXNA1 and PLXNA3 and the symptoms of KS could form the basis of a diagnostic genetic test. "Although KS can be treated with hormone injections if diagnosed early, knowing the underlying genetic causes can make a huge difference to speed up diagnosis and give treatment to the right patients at an earlier time," concludes Professor Anna Cariboni, lead author of the study.


1. Dodé and Hardelin. (2009) Kallmann syndrome. European Journal of Human Genetics. DOI: https://doi.org/10.1038/ejhg.2008.206

2. Oleari et al. (2019) PLXNA1 and PLXNA3 cooperate to pattern the nasal axons that guide gonadotropin-releasing hormone neurons. Development. DOI: https://doi.org/10.1242/dev.176461