Human-chimpanzee differences in a FZD8 enhancer alter cell-cycle dynamics in the developing neocortex

Area of Science:

• Evolutionary biology
• Neuroscience
• Genetics

Background:

• The human neocortex exhibits unique features compared to other great apes, including altered cell cycles and increased size, likely contributing to human cognitive abilities.
• The genetic underpinnings of these evolutionary changes, particularly in non-coding regulatory regions, remain largely unexplored.
• Human-accelerated enhancers have been identified, but their direct link to specific organismal traits is not established.

Purpose of the Study:

• To identify and characterize human-specific regulatory elements that contribute to unique human traits.
• To investigate the role of a novel human-accelerated regulatory enhancer (HARE5) in regulating FZD8 expression during brain development.
• To determine the phenotypic consequences of altered HARE5 activity on brain size and neural progenitor cell dynamics.

Main Methods:

• Identification of HARE5, a human-accelerated regulatory enhancer of FZD8, a Wnt pathway receptor.
• Utilizing transgenic mice to compare the activity of human and chimpanzee HARE5 enhancers.
• Employing chromosome conformation capture assays to assess the physical interaction between HARE5 and the Fzd8 promoter.
• Generating transgenic mice with human (Hs-HARE5) and chimpanzee (Pt-HARE5) enhancers driving Fzd8 expression to evaluate phenotypic effects.

Main Results:

• Human HARE5 demonstrates significantly different activity compared to chimpanzee HARE5, driving early and robust FZD8 expression during corticogenesis.
• HARE5 physically interacts with the Fzd8 promoter in the developing neocortex.
• Transgenic mice expressing Fzd8 under human HARE5 control (Hs-HARE5::Fzd8) exhibit accelerated neural progenitor cell cycles and increased brain size compared to those with chimpanzee HARE5 (Pt-HARE5::Fzd8).

Conclusions:

• HARE5 is a key human-specific regulatory element that influences FZD8 expression during early brain development.
• Altered HARE5 function in humans accelerates neural progenitor cell cycling, potentially contributing to the distinct anatomical features of the human brain.
• This finding provides a direct link between a human-accelerated enhancer and a specific organismal trait, offering insights into the genetic basis of human brain evolution.