ARHGEF6-dependent cytoskeletal regulation underlies a conserved program of forebrain interneuron development

Area of Science:

• Neuroscience
• Developmental Biology
• Genetics

Background:

• Inhibitory interneuron development is critical for forebrain function but poorly understood.
• ARHGEF6, a guanine nucleotide exchange factor linked to X-linked intellectual disability, was previously studied only in postsynaptic compartments.

Purpose of the Study:

• To investigate the role of ARHGEF6 in early forebrain interneuron development.
• To determine if ARHGEF6 has a conserved function across species in neural circuit assembly.

Main Methods:

• Studied ARHGEF6 expression in developing mouse brains.
• Generated and analyzed ARHGEF6-knockout mice.
• Utilized human induced pluripotent stem cell (iPSC)-derived organoids and assembloids from ARHGEF6-knockout individuals.

Main Results:

• ARHGEF6 is selectively enriched in inhibitory interneurons during peak development.
• ARHGEF6 loss in mice caused reduced interneuron numbers, impaired migration, increased cell death, and deficits in maturation.
• Human iPSC-derived models recapitulated these findings, showing increased apoptosis, disorganized growth, and disrupted migration.

Conclusions:

• ARHGEF6 plays an essential, early role in orchestrating inhibitory interneuron development and forebrain circuit assembly.
• Disruption of the ARHGEF6-regulated cytoskeletal program contributes to the excitatory-inhibitory imbalance seen in cognitive dysfunction.
• These findings reveal a conserved molecular mechanism underlying neurodevelopmental disorders.