Madeline Lancaster, from the Institute of Molecular Biotechnology (IMBA) and the MRC Laboratory of Molecular Biology, discussed using cerebral organoids to examine pathogenesis of neurodevelopmental disorders (Lancaster et al., 2013). She noted the many advantages of these self-organizing 3D mixed cultures of human cells, including organized progenitor zones and sequential generation of neuronal layer identities. These organoids comprise radial glia progenitor cells and neurons with good cortical pyramidal morphology. Nonetheless, these mixed cultures lack axis patterning, show high variability (line to line and batch to batch), and show a loss of neurons with extended differentiation. At their current state of development, organoid assays are likely ideal for studying disorders of neurodevelopment (particularly microencephaly), neurogenesis, and fate specification. Noting that microencephaly is not adequately modeled in rodents, Lancaster, in work performed in the lab of Juergen Knoblich, generated hiPSCs from a microencephaly patient with a null mutation in centrosomal protein CDK5RAP2 (independent mutations at either allele). She observed a depleted progenitor population and premature neuronal differentiation, demonstrating the precision of this platform in resolving microencephalic phenotypes.
