Human-Accelerated Enhancer HAR123 Shapes Brain Cell Ratios and Cognitive Flexibility in Mice
CRISPR deletion in mice demonstrates that human-specific changes in HAR123 rewire neural progenitor behavior to shift neuron-glia production ratios, illuminating a molecular entry point for studying human brain evolution.
Overview
- UC San Diego scientists identified HAR123 as a human-accelerated noncoding enhancer that promotes neural progenitor development and neuron-to-glia production ratios in stem-cell assays.
- In vivo CRISPR knockout of HAR123 in mice disrupted neuroectoderm formation and altered neural progenitor clustering, demonstrating its role in early brain development.
- HAR123 knockout mice exhibited impairments in cognitive flexibility tasks, supporting a functional link between this enhancer and adaptive learning behaviors.
- The human HAR123 sequence produced molecular and cellular effects distinct from the chimpanzee version, highlighting species-specific regulatory divergence.
- Researchers plan to test human-mouse enhancer swaps and explore the element’s relevance to neurodevelopmental disorder loci on chromosome 17.