Requirements for the neurodevelopmental disorder-associated gene ZNF292 in human cortical interneuron development and...

Area of Science:

• Neuroscience
• Genetics
• Developmental Biology

Background:

• Pathogenic mutations in ZNF292 are linked to human neurodevelopmental disorders (NDDs).
• The precise functions of ZNF292 in cortical development and its regulatory roles were previously unknown.

Purpose of the Study:

• To investigate the role of ZNF292 in human cortical development using stem cell models.
• To identify the regulatory networks controlled by ZNF292 in neuronal progenitors and mature neurons.

Main Methods:

• Utilized human stem cell models to create ZNF292-deficient cortical inhibitory neuron progenitors and neurons.
• Performed genome-wide occupancy and transcriptomic analyses to identify ZNF292 target genes.
• Assessed neuronal differentiation, maturation, function, and electrophysiological properties.

Main Results:

• ZNF292-deficient progenitors showed precocious differentiation but impaired interneuron maturation and function.
• In progenitors, ZNF292 deficiency upregulated target genes involved in neuronal differentiation and synapse formation.
• In interneurons, ZNF292 deficiency downregulated target genes crucial for maturation and function, including other NDD-related genes, leading to neuronal hyperactivity.

Conclusions:

• ZNF292 is essential for proper human cortical development, particularly for interneuron maturation and function.
• Dysregulation of ZNF292 target genes contributes to the neurodevelopmental deficits observed in ZNF292 mutation-related NDDs.
• This study defines critical neurodevelopmental roles for ZNF292, offering insights into NDD pathogenesis.