The midbrain is one of the earliest‑forming structures of the human brain, and by the second trimester it contains the structures that support vision, sensory processing, cognition and motor control.
To understand how this complexity emerges, researchers at the University of Helsinki and University College London profiled fetal midbrain tissue from six to twenty-two post‑conceptional weeks using a multimodal approach that captured both cellular identity and spatial organization.
Thanks to utilizing both histology, single-cell transcriptomics and spatial transcriptomics, the resulting dataset provides a detailed reference of cell types, developmental trajectories and gene expression dynamics across early human midbrain development.
“To our knowledge, this is the first study to comprehensively study the second gestational trimester of human midbrain development, when key brain structures are formed,” says lead author Pau Puigdevall from the University of Helsinki.
A foundation for future disease modeling
One of the central aims of the study was to understand how dopaminergic neurons diversify and mature. Spatial transcriptomics further provided insight into how migrating neurons organise within the developing midbrain and how similar patterns arise in organoids.
“While there have been many studies focused on the cortex and its development, similar efforts have been lacking in the midbrain, which is highly relevant e.g. for Parkinson’s disease. This study helps address that gap,” says Helena Kilpinen, one of the senior authors of the study.
The researchers compared fetal tissue to two widely used stem cell‑derived midbrain models: two-dimensional dopaminergic neuron cultures and three-dimensional midbrain-like organoids. Both were shown to accurately reproduce early developmental stages, including the emergence of dopaminergic neurons. However, the team identified a divergence point around 10 post‑conceptional weeks, after which fetal transcriptional profiles increasingly differed from the stem-cell derived models.
To test the disease relevance of these models, the team generated midbrain organoids from patients with dopamine transporter deficiency syndrome, a rare childhood‑onset parkinsonian disorder. Importantly, the patient‑derived organoids showed a clear loss of dopaminergic neurons, a hallmark of the disease. This was fully rescued in a cell line where the gene defect was corrected by gene editing methods.
“Despite existing limitations, 3D organoids can recapitulate the loss of dopaminergic neurons, a disease‑specific feature of a Parkinsonian disorder,” notes Pau.
Together, these findings establish a comprehensive framework for understanding human midbrain development and a rigorous benchmark for evaluating stem cell‑derived models. The work lays the groundwork for more accurate modeling of neurodevelopmental and neurodegenerative disorders affecting the dopaminergic system.
Original publication:
Budinger, D., Puigdevall, P., Hall, G.T. et al. An in vivo and in vitro spatiotemporal profile of human midbrain development. Nat Commun (2026).