Single-cell atlas of the developing Down syndrome brain cortex.

Area of Science:

• Neuroscience
• Genetics
• Developmental Biology

Background:

• Down syndrome (DS) is the leading genetic cause of intellectual disability.
• The precise mechanisms by which trisomy 21 disrupts fetal brain development are not fully understood.

Purpose of the Study:

• To investigate the molecular and cellular changes in the developing brain in Down syndrome.
• To identify key genes and regulatory pathways affected by trisomy 21.

Main Methods:

• Single-cell transcriptomic and chromatin accessibility profiling of human fetal cortices from DS and control individuals.
• In vitro studies using antisense oligonucleotides to normalize gene expression in neural progenitors.
• Benchmarking a humanized in vivo model for DS.

Main Results:

• Identified subtype-specific reductions in excitatory neurons (RORB/FOXP1-expressing) and widespread disruption of neurodevelopmental programs.
• Chromosome 21 transcription factors (BACH1, PKNOX1, GABPA) identified as dosage-sensitive regulators of intellectual disability-linked genes.
• In vitro normalization of these TFs partially rescued target gene expression.

Conclusions:

• Defined the gene-regulatory landscape of cortical development in DS.
• Highlighted specific molecular pathways and transcription factors as potential targets for therapeutic investigation in Down syndrome.