Specification of positional identity in forebrain organoids

Nat Biotechnol. 2019 Apr;37(4):436-444. doi: 10.1038/s41587-019-0085-3. Epub 2019 Apr 1.


Human brain organoids generated with current technologies recapitulate histological features of the human brain, but they lack a reproducible topographic organization. During development, spatial topography is determined by gradients of signaling molecules released from discrete signaling centers. We hypothesized that introduction of a signaling center into forebrain organoids would specify the positional identity of neural tissue in a distance-dependent manner. Here, we present a system to trigger a Sonic Hedgehog (SHH) protein gradient in developing forebrain organoids that enables ordered self-organization along dorso-ventral and antero-posterior positional axes. SHH-patterned forebrain organoids establish major forebrain subdivisions that are positioned with in vivo-like topography. Consistent with its behavior in vivo, SHH exhibits long-range signaling activity in organoids. Finally, we use SHH-patterned cerebral organoids as a tool to study the role of cholesterol metabolism in SHH signaling. Together, this work identifies inductive signaling as an effective organizing strategy to recapitulate in vivo-like topography in human brain organoids.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biotechnology
  • Body Patterning
  • Cell Differentiation
  • Cholesterol / metabolism
  • Hedgehog Proteins / metabolism*
  • Humans
  • Mice
  • Models, Neurological
  • Neural Stem Cells / metabolism
  • Neurogenesis
  • Organoids / cytology
  • Organoids / growth & development*
  • Organoids / metabolism*
  • Pluripotent Stem Cells / metabolism
  • Prosencephalon / cytology
  • Prosencephalon / growth & development*
  • Prosencephalon / metabolism*
  • Signal Transduction


  • Hedgehog Proteins
  • SHH protein, human
  • Cholesterol