Specification of positional identity in forebrain organoids

Area of Science:

• Neuroscience
• Developmental Biology
• Stem Cell Biology

Background:

• Current human brain organoids lack reproducible topographic organization despite histological recapitulation.
• In vivo development relies on signaling molecule gradients from discrete centers to establish spatial topography.

Purpose of the Study:

• To investigate if introducing a signaling center into forebrain organoids can specify positional identity and achieve ordered self-organization.
• To establish a system for triggering a Sonic Hedgehog (SHH) protein gradient in organoids.

Main Methods:

• Development of a system to induce a Sonic Hedgehog (SHH) protein gradient in forebrain organoids.
• Analysis of self-organization along dorso-ventral and antero-posterior axes.
• Utilizing SHH-patterned cerebral organoids to study cholesterol metabolism's role in SHH signaling.

Main Results:

• SHH-patterned forebrain organoids demonstrated ordered self-organization along key positional axes.
• Major forebrain subdivisions were established with in vivo-like topography.
• SHH signaling exhibited long-range activity within the organoids, consistent with in vivo observations.

Conclusions:

• Inductive signaling, specifically SHH gradients, is an effective strategy for recapitulating in vivo-like topography in human brain organoids.
• This approach enables the creation of more developmentally relevant brain organoid models.
• SHH-patterned organoids serve as a valuable tool for investigating developmental signaling pathways and related biological processes.