Researchers have identified a group of genes that induces differences in the developing brains of male and female nematodes and triggers the onset of puberty, a genetic pathway that may have the same function in controlling the timing of sexual maturation in humans human.
The study, conducted by scientists at Columbia University, offers new evidence for direct genetic effects in differences based on sex in neural development and provides a basis for trying to understand how the brains of men and women are wired and how they work.
The research was published on January 1 in eLife, an open access journal founded by the Howard Hughes Medical Institute, the Max Planck Society and the Wellcome Trust.
Scientists have long known that puberty is accompanied by substantial changes in the brain characterized by the activation of neurons that produce hormonal signals. But what causes the brain to release the hormones that light up puberty remains elusive.
"In this paper we show that a pathway of regulatory genes acts within specific neurons to induce anatomical and functional differences in the male brain compared to the female brain," said lead author Oliver Hobert, a professor in Department of Biological Sciences of Columbia and a Howard Hughes Medical Institute investigator.
"Surprisingly, we have found that every member of this path is stored between worms and humans, which indicates that we have perhaps discovered a general principle on how the sexual differences in the brain's brain are genetically encoded."
For their study, the researchers worked with the transparent nematode C. elegans
, the first multicellular organism to have sequenced its genome. The worm's genetic makeup is similar to that of humans, making it one of the most powerful research models in molecular genetics and developmental biology.
The research team has identified C. elegans
with a mutation in a single gene known as Lin28. More than a decade ago, scientists discovered a link between mutations in the Lin28 gene and early-onset puberty in adolescent human beings, a highly heritable condition affecting about 5% of the population. Conversely, Lin28 overexpression is also associated with a delay in puberty.
"We knew the gene existed in humans, in mice and worms, but we did not understand how it controlled puberty," Hobert said. "Lin28 worked directly with the brain? What kind of tissue? What other genes did Lin28 control?"
In the mutant analysis C. elegans
strains, the researchers found that worms with precocious puberty carried the mutated Lin28 gene, similar to humans. They also discovered three additional genes associated with premature sexual maturation – the most interesting, the fourth gene, called Lin29.
Lin29 proved to be present only in the male brain and expressed in central neurons, establishing a clear difference in the neural structures of males and females. Even more interesting, male C. elegans
missing the Lin29 gene had a male appearance, but it moved and acted more like the females.
"If you look at animals, including humans, there are dramatic physical and behavioral differences between males and females, including, for example, how they move," Hobert said. "The flawed male worms of Lin29, in essence, were feminized."
Laura Pereira, the first author of the paper and a postdoctoral in the Department of Biological Sciences of Columbia, said that the study is important because it makes clear that there are specific genes that control sexual differences in neural development. "New questions arise about whether differences in male and female behavior are wired into our brains," he said.
The first authors of the document also include Chen Weng and Esther Serrano-Saiz, Columbia University. Other co-authors are Florian Aeschimann and Helge Grosshans, Friedrich Miescher Institute for Biomedical Research, University of Basel, Switzerland, and Hannah Lawson and Douglas S. Portman, University of Rochester.
The research was supported by the Howard Hughes Medical Institute and an R37 grant from the National Institute of Neurological Disorders and Stroke.
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