Changes to just three genetic letters among billions led toevolution and development of the mammalian motor sensory network,and laid the groundwork for the defining characteristics of thehuman brain, Yale University researchers report. This networks provides the direct synaptic connections between themulti-layered neocortex in the human brain responsible foremotions, perception, and cognition and the neural centers of thebrain that make fine motor skills possible. A description of how a few simple changes during the earlydevelopment of mammals led to the creation of complex structuressuch as the human brain was published May 31 in the journal Nature. "What we found are the genetic zip codes that direct cells to formthe motorsensory network of the neocortex," said Nenad Sestan,associate professor of neurobiology, a researcher for the KavliInstitute for Neuroscience, and senior author of the paper The paper investigated the genetic changes that occur during theearly stages of development of an embryo and that direct cells totake on specific functions. Bits of DNA that do not code forproteins, called cis-regulatory elements, have been previouslyidentified as critical drivers of evolution.
These elements controlthe activation of genes that carry out the formation of the basicbody plans of all organisms. Sungbo Shim, the first author, and other members of Sestan's labidentified one such regulatory DNA region, which they named E4,that specifically enhances development of the corticospinal system.E4 is conserved in all mammals, indicating its importance tosurvival, the scientists explain. The lab also discovered how SOX4,SOX11, and SOX5 - sections of DNA called transcription factors -control the expression of genes and operate cooperatively to shapethis network in the developing embryo. The changes in the geneticalphabet needed to trigger these evolutionary changes were tiny,note the researchers.
By manipulating only three genetic letters, scientists were able tofunctionally "jumpstart" regulatory activity in a zebrafish. The authors also show that SOX4 and SOX11 are important for thelayering of the neocortex, an essential change that led toincreased complexity of the brain organization in mammals,including humans. "Together, our fine motor skills that allow us to manipulate tools,walk, speak, and write, as well as our cognitive and emotionalabilities that allow us to think, love, and plan all derive fromthese changes," Sestan said. Sestan's lab is also investigating whether other types of changesin these genes and regulatory elements early in development mightlead to intellectual disability and autism.
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