Autism and Development

Modeling Normal Human Neuron Development and Autism Spectrum Disorders Using Stem Cells

The discovery of human embryonic stem cells (hESCs) and the generation of human induced pluripotent stem cells (hiPSCs) has dramatically expanded our ability to understand the normal development of the human nervous system and the molecular basis of neurodevelopmental disorders. In particular, reprogramming somatic cells into hiPSCs allows generation patient-specific lines of hiPSCs that carry disease causing mutations. One of the most powerful features of hESCs and hiPSCs is their ability to be differentiated into a wide variety of cell types, including neurons. Specific classes of neurons can be generated in abundance for use in biochemical, molecular and cell biological assays of development and function. We are currently using human forebrain neurons, retinal ganglion cells and motorneurons to address both basic and disease related questions concerning the development of the human nervous system.

Current Open Questions:

  1. Are human cortical, motor and retinal neurons sensitive to canonical axon guidance cues?
  2. Do axons of human neurons with mutations in the Tuberous Sclerosis (TSC) related genes, TSC1 and TSC2, exhibit proper axon guidance behaviors in vitro?
  3. What signaling pathway are defective in growth cones of neurons derived from iPSCs of patients with TSC?
  4. Do human cortical neurons with mutations TSC2 exhibit proper axon extension and guidance behaviors within 3D organoids.
  5. Do human neurons generate dendritic spines and are these defective in human neurons with mutations in autism related genes?
  6. Do human neurons with mutations in autism related genes exhibit proper activity in vitro and within 3D organoids?
Human cortical neurospheres extending axons upon pattern stripes of EphrinA1 (red) and Laminin (black). Note on the left are control cortical neurons (corrected TSC2 iPSCs) that avoid EphrinA1 stripes and extend along parallel tracks, while TSC2 mutant cortical neurons (right) are not guided by EphrinA1 stripes.
Canonical signaling downstream of TSC1/TSC2 involves mTOR-mediated protein translation.  However, in addition to this well-studied pathway we have new evidence that TSC1/TSC2 directly activates RhoA to regulate the growth cone cytoskeleton to control axon extension and guidance.