Intrinsic coordination of dynamic molecular signatures shape the human prefrontal cortex

Area of Science:

• Neuroscience
• Genetics
• Developmental Biology

Background:

• The human cerebral cortex, particularly the prefrontal cortex (PFC), is crucial for cognition and executive function.
• The PFC shows unique molecular, structural, and functional characteristics, with disproportionate expansion in humans and vulnerability to neurodevelopmental disorders.
• While 18 molecular signatures of PFC identity are known, the underlying gene networks remain unclear.

Purpose of the Study:

• To investigate the intrinsic gene networks controlling human prefrontal cortex (PFC) molecular identity.
• To identify transcription factors capable of patterning PFC molecular signatures.

Main Methods:

• Pooled CRISPR activation screens in human primary cortical tissues.
• CRISPR screens and knockdown experiments in human cortical organoids.
• Analysis of PFC-enriched transcription factors and their role in activating PFC molecular signatures.

Main Results:

• The neurogenesis regulator YBX1 was identified as a novel factor in activating human PFC fate.
• YBX1 was shown to work with other PFC determinants to activate molecular signatures of PFC identity.
• Evidence supports a model where cohorts of intrinsic determinants orchestrate PFC gene signatures.

Conclusions:

• YBX1 plays a critical role in the intrinsic patterning of human PFC molecular identity.
• Coordinated action of intrinsic determinants ensures robust development of the human PFC.
• Understanding these networks is key to addressing neurodevelopmental disorders affecting the PFC.