Modeling of GATAD2B-associated neurodevelopmental disorder and NuRDopathies: Investigation of cellular & molecular anomalies altering neurodevelopment

Research Objective

Human and animal models of NuRD-deficiency will identify NuRD-subtype function in context of neurogenesis.
Multi-omic studies will identify/quantify molecular and cellular changes in NuRD-deficiency.

Impact

NuRD-deficiency causes several neurodevelopmental disorders (NDDs), our work will identify and quantify cellular and molecular changes in human and mouse models of corticogenesis with NuRD deficiency.

Major Proposed Activities

  • We will generate GAND-IPSCs with inducible expression of HA-GATAD2B to correct these cells' phenotypes seen in NPC growth assays and in the spatial and temporal expression of cortical laminar markers.
  • We will generate GAND-IPSCs with inducible expression of HA-GATAD2A to see if GATAD2B's paralog can function to correct the cellular phenotypes seen in NPC growth and cortical laminar marker assays.
  • GAND-IPSCs with inducible knockdown of GATAD2A will determine if repression of GATAD2A can function to correct the cellular phenotypes seen in NPC growth and cortical laminar marker expression assays.
  • GAND-IPSCs will be used to generate cerebral organoids and using immunohistochemistry will determine if NPC and cortical neuron subtypes are generated and coexpress cortical laminar markers.
  • GAND-IPSCs will be differentiated into cerebral organoids (excitatory/inhibitory) and undergo snRNA-seq/snATAC-seq to identify dysregulated genetic pathways within NPCs/neurons with NuRD-deficiency.
  • Gatad2b-deficient mouse cortices will undergo snRNA-seq/ATAC-seq to identify dysregulated genetic pathways and altered cellular subpopulations in NPCs/neurons to inform/confirm human IPSC data.

Neurodevelopmental disorders (NDDs) affect >3% of the world’s population. Understanding the mechanisms of NDDs is imperative for developing potential therapies to assist families. The focus of our work is the use of patient-derived IPSCs and mouse models to study the epigenetic dysregulation found in NuRD-deficiency and other NDDs. We hope to identify abnormalities in NuRD-deficiency that can be applied to many NDDs, while also fulfilling CIRM’S goal of understanding brain disorders.