Two parallel lineage-committed progenitors contribute to the developing brain.

Area of Science:

• Developmental biology
• Neuroscience
• Evolutionary biology

Background:

• The hindbrain is crucial for life.
• A prevailing model suggests a single neural progenitor forms all brain regions.
• The origin and lineage commitment of distinct brain progenitors remain incompletely understood.

Purpose of the Study:

• To investigate the cellular origins of hindbrain development.
• To challenge the single progenitor model with a dual progenitor hypothesis.
• To explore the evolutionary conservation of brain progenitors.

Main Methods:

• Comparative studies of mouse embryos and human pluripotent stem cells (hPSCs).
• In vitro differentiation assays to assess lineage commitment.
• Chromatin landscape analysis to identify progenitor identity markers.

Main Results:

• Identified two simultaneous, parallel progenitors: anterior neural ectoderm (forebrain/midbrain) and posterior neural ectoderm (hindbrain).
• Demonstrated lineage commitment of these progenitors in vitro.
• Observed distinct chromatin landscapes correlating with forebrain/midbrain vs. hindbrain identities.
• Successfully differentiated hPSCs into hindbrain rhombomere 5/6-specific motor neurons.

Conclusions:

• The brain arises from two distinct, lineage-restricted progenitors, not a single common one.
• These dual progenitors exhibit unique epigenetic signatures.
• This dual progenitor model may be conserved from hemichordates to mammals, over 550 million years.
• The findings facilitate the in vitro generation of specific neuronal subtypes, like hindbrain motor neurons.