Summary:
Challenging centuries of scientific dogma, researchers have discovered that the vertebrate brain does not arise from a single progenitor cell, but instead develops from two distinct, mutually exclusive cell lineages that evolved independently. This developmental divide enabled the team to successfully cultivate authentic human hindbrain neurons in the laboratory for the first time, establishing a new model to study and treat fatal brainstem disorders such as ALS and spinal muscular atrophy.
Key Facts:
- Dual Developmental Origin: Rather than originating from a single ancestral progenitor cell, the brain forms via two parallel lineages: an Otx2-expressing lineage destined for the forebrain and midbrain, and a separate Gbx2-expressing lineage that builds the hindbrain.
- Locked Chromatin Landscapes: The anterior and posterior neural ectoderm exhibit fundamentally distinct chromatin configurations from early gastrulation, explaining why decades of attempts to coax forebrain precursors into hindbrain tissue failed.
- First Authentic Hindbrain Culture: By respecting this early developmental split, researchers successfully directed human pluripotent stem cells to mature into functional, electrically active hindbrain motor neurons that govern swallowing, breathing, and facial movement.
Source: Stanford Medicine
Overturning Centuries of Brain Biology
For centuries, anatomists and neuroscientists have regarded the brain as a singular, continuous organ derived from a common progenitor pool during embryonic development. Textbook models maintained that a primary ancestral lineage simply diversified and branched out to form the complex regional specializations of the nervous system.
Now, a study led by developmental biologists at Stanford Medicine refutes that foundational assumption. Published in Nature Neuroscience, the research shows that what we call the human brain is actually two ancient, independent nervous systems assembled side by side over hundreds of millions of years of evolutionary history.
“We’ve shown for the first time that the front of the brain arises from a totally different progenitor cell than the back of the brain,” said Kyle Loh, Ph.D., associate professor of developmental biology at Stanford Medicine and senior author of the study. “Our discovery means that we can now grow neurons from the back of the brain, the hindbrain, in a petri dish and study their functions.”
Two Lineages on Parallel Tracks
The adult brain is split into three classical divisions: the forebrain, the midbrain, and the hindbrain. While the forebrain governs executive cognition, language, and abstract thought, the hindbrain, commonly known as the brainstem, coordinates the autonomic mechanics necessary for basic survival: rhythmic respiration, cardiac regulation, sleep-wake cycles, metabolic drive, and motor control over facial expression, speech, and swallowing.
Investigating the earliest stages of mouse embryogenesis during gastrulation, co-first authors Rayyan Jokhai and Carolyn Dundes identified two completely non-overlapping progenitor populations:
- Anterior Lineage (Otx2+): Dedicated exclusively to creating the forebrain and midbrain.
- Posterior Lineage (Gbx2+): Committed from the outset to constructing the hindbrain.
These cellular populations never overlap or cross lineages. Epigenomic evaluations revealed that the anterior and posterior neural ectoderm possess distinct chromatin packaging architectures, which permanently lock each cell type into its specific developmental trajectory.
“Previous attempts to make hindbrain neurons likely tried to coax forebrain and midbrain progenitors into hindbrain cells, which our study shows is not possible,” Jokhai explained. “In stem cell biology, people are always fixated with creating the end cell type, like the neuron. But it’s important to begin at the earliest stages of embryonic development. Our careful attention to that early time point allowed us to find this fundamental split.”
A 550-Million-Year-Old Union
To trace the evolutionary origin of this divide, the researchers looked across distant phylogenetic branches. They identified the same dual-origin mechanism in chickens, zebrafish, and even marine acorn worms, which split from our shared lineage over 550 million years ago. More primitive organisms like jellyfish, which diverged 600 to 700 million years ago, feature two separate nervous systems situated at opposite ends of their anatomy.
“Our research suggests that evolution took two existing neural systems and pushed them together spatially,” Loh noted. “Having the brain as one organ would probably be more efficient, but we rely on this primordial way to make the brain as two separate pieces.”
Unlocking In Vitro Models for ALS, SMA, and Metabolic Disease
Armed with the biological blueprint of hindbrain specification, the Stanford investigators guided human pluripotent stem cells into fully functional hindbrain motor neurons. The lab-grown cells displayed normal action potentials and expressed markers characteristic of hindbrain segments controlling facial musculature and swallowing.
The breakthrough provides an experimental platform for studying diseases targeting the brainstem. In disorders such as amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA), degeneration of hindbrain motor neurons robs patients of the ability to swallow and breathe, leading to lethal aspiration pneumonia or respiratory arrest. Because acquiring living brainstem tissue from patients is impossible, medical research has been stalled by a lack of accessible human cellular models.
Beyond motor neuron disease, the system provides insight into metabolic health. The hindbrain houses vital neural circuits that mediate satiety and hunger, the exact pathways modulated by glucagon-like peptide-1 (GLP-1) receptor agonists like semaglutide. Culturing human hindbrain tissue in vitro will allow pharmacologists to directly dissect how hunger-suppressing compounds interact with human brainstem circuits.
“Now we have a model to better understand these devastating diseases, and work toward regenerative therapies for them,” Jokhai said. “This is a very exciting new frontier in 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.
- Journal paper reviewed in full.
- Additional context added by our staff.
About this Genetics and Neurology Research:
- Media Contact: Krista Conger
- Source: Stanford
- Image Credit: Image generated for Neuroscience News
- Original Research is Closed Access: Nature Neuroscience (September 18, 2026). “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
When and how different brain regions diversify from one another remains unresolved. Does a common neural ectoderm progenitor generate the entire brain? Or do multiple neural ectoderm progenitors exist, each restricted to form specific brain regions?
Here our lineage tracing studies of mouse embryos support the latter model. Two parallel brain progenitors emerge simultaneously during gastrulation: anterior neural ectoderm (forebrain/midbrain progenitor) and posterior neural ectoderm (hindbrain progenitor).
Differentiation of human pluripotent stem cells into anterior or posterior neural ectoderm-like cells revealed these were lineage committed to forebrain/midbrain versus hindbrain fates, respectively. They harbored diverging chromatin landscapes foreshadowing future forebrain/midbrain versus hindbrain identities.
We further differentiated human pluripotent stem cells into hindbrain rhombomere 5/6-specific motor neurons, which were hitherto difficult to generate in vitro.
Hence, 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.
