Intrinsic gestational timing governs human cerebellar development after preterm birth
Intrinsic programs shape brain maturation; however, which of these programs are perturbed by prematurity as well as the molecular pathways involved remain unknown. The human cerebellum serves as a paradigm of extrauterine development-its accelerated growth and circuit formation align with the third trimester, a period disrupted by preterm delivery. Using multimodal datasets encompassing in vivo neuroimaging and neurodevelopmental outcomes with postmortem spatial-transcriptomic and histopathological profiling, we show that prematurity diverts the cerebellar developmental trajectory. Cerebellar growth and functional outcomes scaled with gestational age, despite modifying perinatal exposures. Spatially resolved developmental programs underlying macroscopic trajectories were marked by incomplete granule cell maturation and impaired Purkinje cell structural refinement, which indicate lineage-specific developmental asynchrony. Thus, prematurity constitutes biologically displaced maturation, in which infants of equivalent postmenstrual age occupy divergent developmental states.
Authors
- Sniya Valsa Sudhakar (ORCID: https://orcid.org/0000-0002-7632-9705)
- Ioannis Koutroulis (ORCID: https://orcid.org/0000-0002-8396-9022)
- Panagiotis Kratimenos (ORCID: https://orcid.org/0000-0002-7368-0436)
- Rodolfo Cárdenas (ORCID: https://orcid.org/0000-0002-8199-5518)
- Javid Ghaemmaghami (ORCID: https://orcid.org/0000-0002-0122-4466)
- Henrik Sahlin Pettersen (ORCID: https://orcid.org/0000-0003-3219-0577)
- Abhya Vij (ORCID: https://orcid.org/0000-0003-3461-9138)
- Georgios Sanidas (ORCID: https://orcid.org/0009-0004-0105-7380)
- Dimitrios N. Sidiropoulos (ORCID: https://orcid.org/0000-0001-5716-3917)
- Nora S. Wolff (ORCID: https://orcid.org/0000-0003-1729-6453)
- Kyla Woyshner (ORCID: https://orcid.org/0000-0002-1005-9896)
- Kshitij Mankad (ORCID: https://orcid.org/0000-0001-5979-9337)
- Genevieve Stein-O’Brien (ORCID: https://orcid.org/0000-0001-8681-9110)
- Francisco Almeida (ORCID: https://orcid.org/0000-0002-8404-4136)
- Helen J. Chen (ORCID: https://orcid.org/0000-0001-7234-3836)
- Vittorio Gallo (ORCID: https://orcid.org/0000-0002-2429-0845)
- Gabriele Simonti (ORCID: https://orcid.org/0009-0008-5264-2618)
- Robinson Vidva (ORCID: https://orcid.org/0000-0002-2604-5448)
- Maria Triantafyllou (ORCID: https://orcid.org/0009-0008-6123-4384)
- Courtney Lowe (ORCID: https://orcid.org/0000-0001-5117-2118)
- Antonis Polyviou (ORCID: https://orcid.org/0009-0009-8506-4989)
- Daniel Bittel
Institutions
- Children's Hospital of Philadelphia (US)
- Children's National (US)
- Johns Hopkins University (US)
- George Washington University (US)
- University of Washington (US)
- Norwegian University of Science and Technology (NO)
- University of Michigan (US)
- Johns Hopkins Medicine (US)
- Great Ormond Street Hospital (GB)
- St Olav's University Hospital (NO)
- Unidade Local de Saúde de Braga (PT)
- Seattle Children's Research Institute (US)
- Sheikh Zayed Institute for Pediatric Surgical Innovation (US)
- University of Pennsylvania (US)
Publication Details
- Journal
- Science
- Published
- 2026-10-29
- DOI
- https://doi.org/10.1126/science.aeb9095
- Citations
- 1
- Primary Topic
- Neonatal and fetal brain pathology
- Type
- article
- Field-Weighted Citation Impact
- 9.90
Funders
- National Institutes of Health
- Raynor Cerebellum Project