Tiny genomic change makes big difference

A hallmark of mammalian brains is the corticospinal system (CS), which, in humans, connects the cerebral cortex—a part of the brain that is critical for cognition, perception, and behavior—with the motor-sensory centers in the brainstem and the spinal cord, making behaviors such as speech and tool-use possible.

Led by Nenad Sestan, M.D., Ph.D., associate professor of neurobiology, School of Medicine researchers discovered that a genomic region called E4 determines whether the CS emerges during development by exerting regulatory control over the gene Fezf2, which directly mediates CS formation. When the scientists deleted E4, or the transcription factors SOX4 and SOX11 that activate it in mice, the animals lacked CS projections.

In mammals, the E4 region has changed little over evolutionary time, but it varies considerably in other organisms. The new research, published in the May 31 issue of Nature, suggests that a few small sequence changes in the E4 region marked a crucial turning point in the evolution of mammals.