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Emergence of the ZNF675 Gene During Primate Evolution-Influenced Human Neurodevelopment Through Changing HES1
Gerrald A Lodewijk1, Matthijs de Geus1, Rita L F P Guimarães1
1Swammerdam Institute for Life Sciences, Evolutionary Neurogenomics, University of Amsterdam, Amsterdam, The Netherlands.
The Journal of Comparative Neurology
|July 3, 2024
Summary
Recurrent copy number variations in ZNF675 are linked to neurodevelopmental disorders. This study shows ZNF675 deletion causes defects in brain organoids by disrupting HES1 regulation, highlighting its role in human brain development.
Area of Science:
- Genetics
- Neuroscience
- Developmental Biology
Background:
- Recurrent copy number variations (CNVs) at the 19p12 locus are associated with neurodevelopmental disorders.
- The primate-specific genes ZNF675 and ZNF681, located in this locus, are implicated in human brain development.
- Krüppel-associated box zinc finger (KZNF) proteins are transcriptional repressors involved in epigenetic silencing, with emerging roles in gene regulation.
Purpose of the Study:
- To investigate the role of ZNF675 and ZNF681 in neurodevelopment.
- To determine the functional impact of ZNF675 copy number variations on brain development.
- To elucidate the molecular mechanisms by which ZNF675 influences neurodevelopmental gene regulation.
Main Methods:
- Analysis of copy number variations (CNVs) in the 19p12 locus.
- Generation and analysis of cortical organoids with genetic deletion of ZNF675.
- Investigation of ZNF675's regulatory role on neurodevelopmental genes, including HES1.
Main Results:
- Genetic deletion of ZNF675 leads to developmental defects in cortical organoids.
- ZNF675 regulates the promoter of Hes family BHLH transcription factor 1 (HES1), a key neurodevelopmental gene.
- ZNF675 interferes with HES1 auto-inhibition, impacting neural progenitor maintenance and altering HES1 autoregulation.
Conclusions:
- ZNF675 plays a critical role in human brain development.
- Alterations in ZNF675 copy number can lead to neurodevelopmental disorders.
- The emergence of ZNF675 has influenced HES1 autoregulation, contributing to the evolution of human brain development.
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