Timing mechanism of sexually dimorphic nervous system differentiation

In most adult animals, male and female brains are slightly different. For example, in the nematode worm Caenorhabditis elegans, certain neurons exist in one sex but not the other. Nerve cells that are shared in both sexes may also activate different genes, or form different connections in males and females. Most of these differences – which ultimately give rise to sex-specific behaviors – emerge during a period of development called sexual maturation. Yet, the mechanisms that control when sexual differentiation takes place in the brain are largely unknown. To investigate this, Pereira et al. set out to determine how sex differences arise in the nervous system of C. elegans, a small animal with two sexes, male and hermaphrodite. In particular, Pereira et al. wanted to know which genes cause certain neurons that are present in both sexes to switch to the male-specific form when the worm gets old enough. The experiments revealed that a genetic pathway formed of three genes, let-7, lin-28 and lin-41, controls when sexual maturation takes place throughout the worm nervous system. When the worm is young, lin-41 is active and represses a gene called lin-29A. As the animal reaches maturity, let-7 ‘switches off’ lin-41, and lin-29A gets activated in a subset of neurons. These brain cells then turn on male-specific genes and acquire a shape only found in males. The anatomy of male mutant worms that lack lin-29A is normal, but the animals show features found in hermaphrodites, for example in the way they crawl across a dish. This shows that activating lin-29A may also trigger male-specific behaviors. Switching on sex-specific neuronal circuits at the correct time is essential for animals to develop correctly. The lin-7 and let-28 genes also control when sexual maturation takes place in mammals, so studying these genes in C. elegans could help to understand how male and female brains are shaped during development in other species, and why some diseases affect the sexes differently.