Intrinsic Gestational Timing Governs Human Cerebellar Development After Preterm Birth

Abstract Intrinsic programs govern brain maturation, but whether preterm birth induces a persistent shift in these processes remains unknown. The human cerebellum provides a model of extrauterine development; its most rapid growth and circuit maturation occur during the third trimester, a period disrupted by early delivery. By leveraging multimodal in vivo and postmortem tissue analyses, we show that preterm birth constrains cerebellar maturation. Cerebellar growth and functional outcomes scaled with gestational age at birth, paralleled by cellular and spatial molecular programs marking incomplete granule cell maturation and impaired Purkinje cell structural refinement. These lineage-specific alterations indicate developmental asynchrony in prematurity. Thus, in preterm infants, gestational age at birth establishes a cerebellar maturational ceiling, such that postnatal age does not correspond to biological maturity. Competing Interest Statement The authors have declared no competing interest. Footnotes This revised manuscript includes extensive new data and analyses. Major additions: (1) Integrated in vivo analysis combining term-equivalent MRI volumetrics, longitudinal cranial ultrasonography, and standardized neurodevelopmental follow-up, linking cerebellar growth trajectories with functional outcomes. (2) Independent cohort validation ensuring robustness and generalizability of principal findings. (3) Expanded orthogonal molecular validation using RNAscope and immunostaining, providing single-cell resolution in situ confirmation of spatial transcriptomic findings. (4) Population-level validation through GWAS analyses linking identified developmental programs to determinants of cerebellar structure and function.