Two parallel lineage-committed progenitors contribute to the developing brain

Carolyn E Dundes; Rayyan T Jokhai; Hadia Ahsan; Rachel S Kang; Rachel E A Salomon-Shulman; Arjun Rajan; Yoon Seok Kim; Liam J Stanton; Christine Xu; Stephanie Do; Brennan D McDonald; José Miguel Andrade López; Hugo A Urrutia; Hannah Greenfeld; Alicia Wong; Yimiao Qu; Andrew S Petkovic; Yi Miao; K Christopher Garcia; Michelle Monje; Daniel E Wagner; Marianne E Bronner; Christopher J Lowe; Kyle M Loh

doi:10.1101/2025.07.02.662771

Two parallel lineage-committed progenitors contribute to the developing brain

bioRxiv [Preprint]. 2025 Jul 5:2025.07.02.662771. doi: 10.1101/2025.07.02.662771.

Authors

Carolyn E Dundes^{1

2}, Rayyan T Jokhai^{1

2}, Hadia Ahsan^{1

2}, Rachel S Kang^{1

2}, Rachel E A Salomon-Shulman^{1

2}, Arjun Rajan^{1

2}, Yoon Seok Kim^{2

3}, Liam J Stanton^{1

2}, Christine Xu^{1

2}, Stephanie Do^{1

2}, Brennan D McDonald⁴, José Miguel Andrade López⁴, Hugo A Urrutia⁵, Hannah Greenfeld⁶, Alicia Wong^{1

2}, Yimiao Qu^{1

2}, Andrew S Petkovic^{1

2}, Yi Miao⁷, K Christopher Garcia⁷, Michelle Monje^{2

3}, Daniel E Wagner⁶, Marianne E Bronner⁵, Christopher J Lowe⁴, Kyle M Loh^{1

2}

Affiliations

¹ Department of Developmental Biology, Stanford University, Stanford, CA USA.
² Institute for Stem Cell Biology & Regenerative Medicine, Stanford University, Stanford, CA USA.
³ Department of Neurology and Neurological Sciences, Howard Hughes Medical Institute, Stanford University, Stanford, CA USA.
⁴ Hopkins Marine Station, Department of Biology, Stanford University, Pacific Grove, CA USA.
⁵ Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA USA.
⁶ Department of Obstetrics, Gynecology and Reproductive Science, Center for Reproductive Sciences, Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, University of California San Francisco, San Francisco, CA, USA.
⁷ Department of Molecular and Cellular Physiology, Department of Structural Biology, Howard Hughes Medical Institute, Stanford University, Stanford, CA, USA.

Abstract

The hindbrain is a life-sustaining brain region. In one model, a common neural progenitor generates all brain regions. Here our studies of mouse embryos and human pluripotent stem cells (hPSCs) support a different model: two parallel brain progenitors emerge simultaneously during gastrulation, anterior neural ectoderm (forebrain/midbrain progenitor) and posterior neural ectoderm (hindbrain progenitor). Not only are they lineage-committed to respectively form forebrain/midbrain vs. hindbrain in vitro, but they also have diverging chromatin landscapes foreshadowing future forebrain/midbrain vs. hindbrain identities. Leveraging these differences, we differentiated hPSCs into hindbrain rhombomere 5/6-specific motor neurons, hitherto difficult to generate in vitro. We postulate the brain is a composite organ emanating from two lineage-restricted progenitors; these dual progenitors may be evolutionarily conserved across 550 million years from hemichordates to mammals.

Publication types

Preprint

Abstract

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