Early Developmental Origins of Cortical Disorders Modeled in Human Neural Stem Cells

Area of Science:

• Developmental Neuroscience
• Genetics of Neurodevelopmental Disorders
• Stem Cell Biology

Background:

• The role of early human telencephalic development, particularly neural stem cells (NSCs), in the origin of cortical disorders is not well understood.
• Identifying critical developmental periods and genetic factors contributing to these disorders is crucial for understanding their etiology.

Purpose of the Study:

• To investigate the expression patterns of genes linked to cortical and neuropsychiatric disorders during human NSC development.
• To identify critical developmental windows and gene regulatory networks associated with NSC vulnerability in disease contexts.
• To explore the impact of genetic perturbations on developing human neocortical cell types.

Main Methods:

• Analysis of gene expression datasets from human NSCs undergoing telencephalic fate transitions in vitro and in vivo.
• Identification of gene regulatory networks and disease-specific critical phases during corticogenesis.
• In silico simulation of transcription factor (TF) depletion effects on developing neocortical cell types.
• Single-cell transcriptomics of patient-derived NSCs to identify alterations in brain patterning and lineage commitment TFs.

Main Results:

• Identified risk genes in brain organizers and sequential gene regulatory networks across corticogenesis.
• Revealed disease-specific critical phases where NSCs are vulnerable to gene dysfunction, with converging signaling across disorders.
• Demonstrated spatiotemporal-dependent effects of simulated TF depletions on developing human neocortical cell types.
• Discovered recurrent alterations in TFs controlling brain patterning and NSC lineage commitment in autism patient-derived NSCs.

Conclusions:

• Early human brain development, particularly NSC behavior, is critical for understanding cortical and neuropsychiatric disorders.
• This study identifies vulnerable developmental stages and key genetic regulators, offering new avenues for exploring brain dysfunction origins.
• Findings provide a foundation for future research into the early etiological phases of human brain disorders.