Is the brain really two organs in one?

Clinical takeaway: The neurons that degenerate in SMA and ALS can now be made from stem cells, giving researchers their first direct window on these diseases in the human cells they attack. 

The brainstem does the body's least glamorous and most essential work. Its neurons drive breathing, swallowing, sleep and heart rate, and when they degenerate, as they do in spinal muscular atrophy and amyotrophic lateral sclerosis, patients lose the ability to swallow and eventually to breathe. Studying that degeneration directly has been nearly impossible: brainstem tissue cannot be sampled from living patients, and for decades the hindbrain motor neurons at the center of these diseases resisted every attempt to grow them from stem cells while forebrain and midbrain neurons grew readily. 

Stem cell protocols rested on a longstanding model in which a single progenitor cell gives rise to the entire brain, so a recipe that produced one brain region should have been tunable to produce any other. Researchers now report on why that assumption failed: the brain arises from two separate progenitor cell populations, locked into their fates from the earliest stage of development, and the standard recipes were aimed at the wrong one. 

The team traced the brain's origins to two mutually exclusive progenitor populations that appear during gastrulation, the stage when the body plan first takes shape. One, marked by the gene Otx2, produces the forebrain and midbrain; the other, marked by Gbx2, produces the hindbrain. Lineage tracing in mouse embryos tracked 494 neural ectoderm-derived cell clusters across 16 embryos: 62.96% mapped to the forebrain and midbrain and 32.59% to the hindbrain. The remaining 4.45% spanned both. 

Each population carries a distinct chromatin configuration that locks its fate: when the researchers challenged hindbrain progenitors with forebrain-inducing signals in vitro, the cells refused the cue and activated hindbrain regulatory programs instead, and the reverse held for forebrain progenitors pushed toward hindbrain identity. The same two-population split appeared in gastrulating macaque, chicken and zebrafish embryos, and in the acorn worm, a hemichordate whose lineage diverged from ours roughly 550 to 600 million years ago. 

Applying the insight, the team produced what standard protocols never could: human hindbrain motor neurons, grown from pluripotent stem cells by adding FGF and retinoic acid to the usual neural induction signals. The neurons fired action potentials and expressed markers specific to rhombomeres 5 and 6, the hindbrain segments whose motor neurons control swallowing, the same cell types that degenerate in SMA and ALS. 

The findings rest on genetic lineage tracing in mouse embryos, using two complementary Cre-driver systems to label progenitor populations during gastrulation, paired with directed differentiation of human pluripotent stem cells across four independent lines. Chromatin accessibility was profiled by ATAC sequencing. The evolutionary comparisons drew on new and previously published single-cell data from macaque, chicken and zebrafish embryos, plus in situ staining of acorn worm embryos. 

The team plans to trace the developmental origin of the spinal cord and to work out how SMA and ALS compromise hindbrain neuron function, now that the affected cells can be studied directly. Open questions remain within the hindbrain itself. Lineage tracing suggests the posterior progenitor contributes mainly to the posterior hindbrain, and the origin of the anterior-most hindbrain, including the cerebellum, is unresolved. The authors raise the possibility of a third, undiscovered progenitor. 

"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, PhD, associate professor of developmental biology at Stanford Medicine. "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." 

Source: Jokhai RT, et al. (2026 Sep 18) Nat Neurosci. Two parallel neural ectoderm progenitors contribute to the developing brain