Intrinsic Gestational Timing Governs Human Cerebellar Development After Preterm Birth

Intrinsic biological clocks govern human brain development, but whether these programs recover from early disruption, such as premature birth, remains unknown. The cerebellum, with peak maturation in the last trimester, provides a model to address this challenge. We analyzed an unprecedented combination of in-vivo and postmortem cohorts of human postnatal cerebella spanning 22-42 weeks’ gestation, integrating longitudinal neuroimaging, spatial transcriptomics, and machine-learning-based histology to capture developmental states inaccessible to experimental models. Gestational age imposed lasting differences in postnatal cerebellar growth, architecture, and molecular programs. Spatially resolved gene expression data revealed lineage-specific rules: granule cells followed an immutable developmental clock, whereas Purkinje cells failed to undergo the maturation-linked reduction in cell numbers, retaining their population but with reduced dendritic complexity, reflected by a thinner molecular layer after early extrauterine transition. These findings redefine prematurity as a state-dependent arrest of intrinsic brain programs and provide a foundation for regenerative and neuroprotective interventions.