DCHS1 Modulates Forebrain Proportions in Modern Humans via a Glycosylation Change

Area of Science:

• Evolutionary biology
• Neuroscience
• Genetics

Background:

• Modern human brains exhibit a disproportionately enlarged neocortex compared to the striatum, a trait distinguishing them from primates and extinct hominins.
• Understanding the molecular underpinnings of this unique human brain organization is crucial for evolutionary and developmental neuroscience.

Purpose of the Study:

• To investigate the molecular basis for the expanded neocortex relative to the striatum in modern humans.
• To identify specific genetic mutations unique to modern humans that influence brain structure.

Main Methods:

• Screening for high-frequency, human-specific missense mutations affecting post-translational sites, focusing on the DCHS1 gene.
• Utilizing CRISPR/Cas9 gene editing in human-induced pluripotent stem cells (hiPSCs) to revert DCHS1 to its ancestral primate/Neanderthal variant.
• Employing hiPSCs-derived neural organoids to model early human brain development and assess anatomical changes.

Main Results:

• A specific DCHS1 mutation, disrupting an N-glycosylation site, was identified as unique to modern humans.
• Reintroducing the ancestral DCHS1 variant into hiPSCs resulted in neural organoids showing an expansion of striatal progenitors at the expense of the neocortex.
• Ephrin receptor EPHA4 was identified as a DCHS1 binding partner, with human-specific DCHS1 alterations modulating EPHA4-ephrin signaling.

Conclusions:

• Modern human-specific alterations in DCHS1 play a significant role in shaping the neocortex-to-striatum ratio during brain development.
• The modulation of EPHA4-ephrin signaling by DCHS1 contributes to the distinct brain organization observed in modern humans.
• This study provides molecular insights into the evolutionary trajectory of the human brain, highlighting the role of specific gene changes in anatomical divergence.