Recapitulating cortical development with organoid culture in vitro and modeling abnormal spindle-like (ASPM related primary) microcephaly disease

Protein Cell. 2017 Nov;8(11):823-833. doi: 10.1007/s13238-017-0479-2. Epub 2017 Oct 23.


The development of a cerebral organoid culture in vitro offers an opportunity to generate human brain-like organs to investigate mechanisms of human disease that are specific to the neurogenesis of radial glial (RG) and outer radial glial (oRG) cells in the ventricular zone (VZ) and subventricular zone (SVZ) of the developing neocortex. Modeling neuronal progenitors and the organization that produces mature subcortical neuron subtypes during early stages of development is essential for studying human brain developmental diseases. Several previous efforts have shown to grow neural organoid in culture dishes successfully, however we demonstrate a new paradigm that recapitulates neocortical development process with VZ, OSVZ formation and the lamination organization of cortical layer structure. In addition, using patient-specific induced pluripotent stem cells (iPSCs) with dysfunction of the Aspm gene from a primary microcephaly patient, we demonstrate neurogenesis defects result in defective neuronal activity in patient organoids, suggesting a new strategy to study human developmental diseases in central nerve system.

Keywords: ASPM; cerebral organoid; microcephaly; neocortical development.

MeSH terms

  • Action Potentials / physiology
  • Biomarkers / metabolism
  • Cell Culture Techniques
  • Embryoid Bodies / cytology
  • Embryoid Bodies / metabolism
  • Gene Expression
  • Humans
  • Induced Pluripotent Stem Cells / cytology*
  • Induced Pluripotent Stem Cells / metabolism
  • Lateral Ventricles / cytology*
  • Lateral Ventricles / growth & development
  • Lateral Ventricles / metabolism
  • Microcephaly / genetics
  • Microcephaly / metabolism
  • Microcephaly / pathology*
  • Models, Biological*
  • Mutation
  • Neocortex / cytology
  • Neocortex / growth & development
  • Neocortex / metabolism
  • Nerve Tissue Proteins / deficiency
  • Nerve Tissue Proteins / genetics*
  • Neurogenesis / genetics
  • Neurons / cytology
  • Neurons / metabolism
  • Organoids / cytology*
  • Organoids / metabolism
  • PAX6 Transcription Factor / genetics
  • PAX6 Transcription Factor / metabolism
  • Patch-Clamp Techniques
  • SOXB1 Transcription Factors / genetics
  • SOXB1 Transcription Factors / metabolism
  • Zonula Occludens-1 Protein / genetics
  • Zonula Occludens-1 Protein / metabolism


  • ASPM protein, human
  • Biomarkers
  • Nerve Tissue Proteins
  • PAX6 Transcription Factor
  • PAX6 protein, human
  • SOX2 protein, human
  • SOXB1 Transcription Factors
  • TJP1 protein, human
  • Zonula Occludens-1 Protein