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Fate plasticity of interneuron specification.

Mohammed A Mostajo-Radji1,2,3, Walter R Mancia Leon1,4, Arnar Breevoort1,2

  • 1The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143, USA.

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Summary

Environmental signals shape neuronal identity. Mouse medial ganglionic eminence progenitors generated specific cortical interneurons, with human brain organoids promoting efficient parvalbumin-positive interneuron development.

Keywords:
Biological sciencesCellular neuroscienceNatural sciencesNeuroscienceSystems neuroscience

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Area of Science:

  • Neuroscience
  • Developmental Biology
  • Genetics

Background:

  • Neuronal subtype generation in the mammalian central nervous system is controlled by genetic programs.
  • The medial ganglionic eminence (MGE) generates somatostatin (Sst) and parvalbumin (Pvalb) cortical interneuron (IN) populations with distinct developmental timelines.
  • The influence of external signals on IN subtype identity is not fully understood, and Pvalb-positive INs are difficult to model in vitro.

Purpose of the Study:

  • To investigate the influence of microenvironmental cues on the differentiation of MGE-derived INs.
  • To explore the potential for in vitro modeling of Pvalb-positive IN development using diverse co-culture systems.
  • To determine if Sst-positive INs exhibit fate plasticity in response to specific environmental signals.

Main Methods:

  • Grafting of mouse MGE progenitors into various 2D and 3D co-culture systems, including mouse and human cortical, MGE, and thalamic models.
  • Analysis of Pvalb differentiation markers, Sst-specific markers, and perineuronal net formation.
  • Lineage tracing of postmitotic Sst-positive INs grafted onto human cortical models.

Main Results:

  • Three-dimensional human corticogenesis models significantly promoted Pvalb differentiation and maturation.
  • These models led to the downregulation of Sst markers and the formation of perineuronal nets.
  • Lineage-traced Sst-positive INs demonstrated Pvalb upregulation when exposed to the human cortical environment, indicating fate plasticity.

Conclusions:

  • The microenvironment plays a critical role in shaping the identity of MGE-derived INs.
  • Human 3D corticogenesis models offer a promising platform for studying Pvalb-positive IN development.
  • MGE-derived INs exhibit remarkable environmental plasticity, challenging the notion of fixed developmental trajectories.