Summary:
Challenging long-held assumptions about brain development, researchers have shown that the vertebrate brain does not arise from a single ancestral progenitor. Instead, it develops from two distinct, mutually exclusive lineages that diverged early in evolution. This discovery allowed scientists to grow authentic human hindbrain neurons in the laboratory for the first time, creating a new in vitro model to study and potentially treat life-threatening brainstem disorders such as amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA).
Key Facts:
- Dual Developmental Origin: The brain forms from two parallel progenitor lineages: an Otx2-expressing anterior lineage that produces forebrain and midbrain structures, and a separate Gbx2-expressing posterior lineage committed to the hindbrain.
- Distinct Chromatin Landscapes: From early gastrulation, anterior and posterior neural ectoderm exhibit fundamentally different chromatin configurations, which lock cells into their respective developmental fates and explain why prior attempts to convert forebrain precursors into hindbrain cells were unsuccessful.
- First Reliable Hindbrain Culture: Respecting this developmental split, investigators directed human pluripotent stem cells to differentiate into electrically active hindbrain motor neurons that control swallowing, breathing, and facial movement.
Source: Stanford Medicine
Overturning a Core Assumption in Brain Biology
For centuries, anatomy and developmental biology taught that the brain emerges from a single, continuous pool of progenitor cells that later diversify to form different regions. New research from Stanford Medicine overturns that model. Published in Nature Neuroscience, the study provides evidence that the brain is a composite organ made from two independent neural systems assembled side by side during embryogenesis.
“We demonstrate that the front of the brain arises from a completely different progenitor than the back,” said Kyle Loh, Ph.D., associate professor of developmental biology at Stanford Medicine and senior author of the study. “Recognizing this split enabled us to grow hindbrain neurons in vitro and study their unique properties.”
Two Lineages Running in Parallel
The mature vertebrate brain is traditionally divided into forebrain, midbrain, and hindbrain. The forebrain supports higher cognitive functions—reasoning, language, and decision-making—while the hindbrain, or brainstem, controls essential autonomic functions including respiration, cardiac regulation, sleep–wake cycles, metabolic drive, and motor control of facial expression, speech, and swallowing.
By examining mouse embryos during gastrulation, co-first authors Rayyan Jokhai and Carolyn Dundes identified two non-overlapping progenitor populations:
- Anterior Lineage (Otx2+): Dedicated to forming forebrain and midbrain structures.
- Posterior Lineage (Gbx2+): Committed from the start to build the hindbrain.
These progenitor pools remain separate throughout early development. Epigenomic profiling showed that anterior and posterior neural ectoderm possess distinct chromatin architectures that predispose each population to its specific developmental trajectory.
“Many earlier efforts attempted to coax forebrain or midbrain cells into hindbrain identities,” Jokhai explained. “Our work shows that such conversions are unlikely because the cells are epigenetically committed from very early stages. To make authentic hindbrain neurons, you must begin with the correct posterior progenitor program.”
An Evolutionary Union Dating Back Hundreds of Millions of Years
To investigate the evolutionary roots of this division, the team surveyed species across distant branches of the animal kingdom. They found evidence for the same dual-origin mechanism in chickens, zebrafish, and even hemichordates such as acorn worms—organisms whose lineages split from ours more than 550 million years ago. More ancient animals, like some cnidarians, also show separate neural systems at opposite body ends.
“Evolution appears to have brought two ancestral neural systems into proximity, forming the composite brain we recognize in vertebrates,” Loh said. “Although a single, unified brain might seem more efficient, the developmental program built on two distinct origins persists across deep evolutionary time.”
Creating Human Hindbrain Models to Study Disease and Metabolism
Using the molecular blueprint for hindbrain specification, researchers guided human pluripotent stem cells into hindbrain-specific motor neurons, particularly those corresponding to rhombomere 5/6—cells that were previously difficult to produce in vitro. These lab-grown neurons showed normal electrophysiological activity and expressed markers characteristic of hindbrain segments that control facial muscles and swallowing.
This advance establishes an experimentally tractable human model for brainstem disorders. In ALS and SMA, progressive degeneration of hindbrain motor neurons impairs patients’ ability to swallow and breathe, often resulting in fatal aspiration pneumonia or respiratory failure. Because human brainstem tissue is inaccessible in living patients, developing authentic hindbrain cultures removes a major barrier to studying disease mechanisms and testing therapies.
Beyond neurodegeneration, the hindbrain hosts circuits that regulate hunger and satiety—pathways targeted by GLP-1 receptor agonists such as semaglutide. Cultured human hindbrain tissue offers pharmacologists a direct way to study how appetite-suppressing drugs interact with brainstem circuits, potentially improving metabolic and obesity treatments.
“We now have a model to investigate devastating brainstem disorders and pursue regenerative strategies,” Jokhai said. “This opens a new and promising frontier for translational brain research.”
Funding: This work was supported by the National Institutes of Health (grants DP5OD024558, DP2GM146258, R00GM121852, R01DK115728, R01DE027538, T32GM119995, T32GM007365, T32GM007790 and F31DE031154); the National Science Foundation; the California Institute for Regenerative Medicine; the Spinal Muscular Atrophy Foundation; a Stanford Maternal and Child Health Research Institute grant; the Stanford Beckman and Ludwig Centers; the Siebel Stem Cell Institute; a Stinehart-Reed Foundation grant; the Gatsby Charitable Foundation; the Howard Hughes Medical Institute; the Packard Foundation; the Pew Charitable Trusts; the Baxter Foundation; the Human Frontier Science Program; and the anonymous, Fickel, Gilbert, and Stinehart-Reed families.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- The journal paper was reviewed in full.
- Additional scientific and contextual details were added by staff editors.
About this Genetics and Neurology Research:
- Media Contact: Krista Conger
- Source: Stanford
- Image Credit: Image generated for Neuroscience News
- Original Research (Closed Access): Nature Neuroscience (September 18, 2026). Title: “Two parallel neural ectoderm progenitors contribute to the developing brain.” Authors: Rayyan T. Jokhai, Carolyn E. Dundes, Hadia S. 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: 10.1038/s41593-026-02433-7
Abstract
Two parallel neural ectoderm progenitors contribute to the developing brain
The timing and mechanisms by which distinct brain regions diverge have remained unclear. Do all regions arise from a single neural ectoderm progenitor, or do multiple progenitors exist that are each restricted to specific brain regions? Our lineage-tracing studies in mouse embryos support the latter: two parallel brain progenitors emerge at gastrulation—an anterior neural ectoderm progenitor for forebrain and midbrain, and a posterior neural ectoderm progenitor for the hindbrain.
Differentiation of human pluripotent stem cells into anterior-like or posterior-like neural ectoderm revealed lineage commitment consistent with future forebrain/midbrain versus hindbrain identities. These populations displayed divergent chromatin landscapes that foreshadowed their regional fates.
We further directed human pluripotent stem cells to form hindbrain rhombomere 5/6-specific motor neurons, a cell type previously difficult to generate in vitro.
Together, these results support a model in which the brain is a composite organ assembled from two lineage-restricted progenitors, and suggest this dual-origin strategy is evolutionarily conserved across roughly 550 million years from hemichordates to mammals.