Sex differences in a sensory system

Two signals work together to create different patterns of sensory nerves in male and female mice.
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Image credit: Vered Shacham-Silverberg (CC BY 4.0)

Almost every action an animal can perform in its life will rely on its nervous system being wired correctly. Before the animal is born, nerve cells next to the spinal cord send out long fibers – called axons – to connect with different parts of its body. These nerves will help relay sensations to the brain. The ends of the nerve fibers follow trails of signals that guide them to the correct targets. When the axon arrives in the right place, it can receive further signals called neurotrophic factors. These signals keep the axon alive, but they are in short supply. Not every axon will receive the signal, and, without it, the nerve fiber dies back. This phenomenon, known as pruning, helps to make sure that nervous system does not form more connections than it needs.

In mammals, the mammary gland is an example of a part of the body where nerve endings are pruned during development. Axons that connect to this milk-producing gland depend on a neurotrophic factor called BDNF to survive, and BDNF is controlled differently in males and females. In male mammals, another protein grabs hold of the BDNF signal and hides it away before development is complete. After this happens, the axons start to die, however it was not clear if other signals are also involved.

Sar Shalom et al. have now examined if proteins called Semaphorins – which guide axons to their target locations and influence pruning too – also control how many nerves end up connected to the mammary gland. The experiments used nerve cells grown in the laboratory and genetically modified mice, and suggested that the nerves in the mammary gland would only develop correctly if the BDNF and Semaphorins signals were properly balanced.

When the lab-grown nerve cells encountered Semaphorins, their growing axons collapsed. Yet unlike for BDNF, the levels of Semaphorins were the same in male and female mice. Further experiments showed that if a protein receptor that detects the Semaphorins was deleted, the nerve cells stopped responding to the signal, and their axons did not collapse. In mice lacking this receptor, both sexes ended up with more axons in their mammary glands. Too many axons grew in the female mice, while the pruning of excess axons was delayed in the males. Reducing the levels of BDNF in these mice helped to return axon growth to normal. Together, these findings suggest that a balance between the BDNF and the Semaphorins sets the correct number of nerves. They also suggest that once the BNDF signal is removed during the normal development of males, it is the Semaphorins that help the axons in the mammary gland to be pruned.

Lastly, neurotrophic factors and Semaphorins are not just important during development; indeed cells make them well into adulthood. Altered patterns of these signals in mature animals could change the shapes of nerve networks. As such, future work may help scientists to understand why tissues can become too sensitive or lose sensation.