22q11 deletion selectively alters progenitor states and projection neuron identities in the developing cerebral cortex

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Abstract
Heterozygous deletion of multiple contiguous genes associated with 22q11.2 Deletion Syndrome (22q11DS), a developmental disorder with significant risk for autistic spectrum disorder (ASD) and schizophrenia (Scz), selectively compromises neurogenic capacities of a temporally distinct cohort of cerebral cortical basal progenitors (bPs), prefiguring diminished frequency, divergent times of origin, positions, and identities of a subset of Layer 2/3 projection neuron (PN) progeny in the LgDel 22q11DS mouse model. LgDel bPs express 24/28 contiguous murine 22q11 gene orthologues at diminished levels; in parallel, cell cycle kinetics, modes of division, gene expression levels, and DNA methylation states are aberrant in LgDel bPs but not their apical progenitor precursors. Accordingly, targeted disruption of bP proliferative and transcriptional states selectively alters Layer 2/3 PN identities and frequencies, prefiguring atypical association cortico-cortical connections and behavioral deficits associated with ASD and Scz pathology in a mouse model of 22q11DS.
Funding Information
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01 HD042182)
  • Seale Innovation Fund
  • Red Gates Foundation

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