The human neonatal cerebellum is a fourth of its adult size, yet contains the blueprint required to integrate environmental cues with developing motor, cognitive, and emotional skills into adulthood. Although mature cerebellar neuroanatomy is well studied, understanding its developmental origins is limited. Here, we systematically mapped the molecular, cellular, and spatial composition of human fetal cerebellum by combining laser capture microscopy and SPLiT-seq single-nucleus transcriptomics. We profiled functionally distinct regions and gene expression dynamics within cell types and across development. The resulting cell atlas demonstrates that the molecular organization of the cerebellar anlage recapitulates cytoarchitecturally distinct regions and developmentally transient cell types that are distinct from the mouse cerebellum. By mapping genes dominant for pediatric and adult neurological disorders onto our dataset, we identify relevant cell types underlying disease mechanisms. These data provide a resource for probing the cellular basis of human cerebellar development and disease.

We present histological and molecular analyses of the developing human cerebellum from 30 days after conception to 9 months after birth. Differences in developmental patterns between humans and mice include spatiotemporal expansion of both ventricular and rhombic lip primary progenitor zones to include subventricular zones containing basal progenitors. The human rhombic lip persists longer through cerebellar development than in the mouse and undergoes morphological changes to form a progenitor pool in the posterior lobule, which is not seen in other organisms, not even in the nonhuman primate the macaque. Disruptions in human rhombic lip development are associated with posterior cerebellar vermis hypoplasia and Dandy-Walker malformation. The presence of these species-specific neural progenitor populations refines our insight into human cerebellar developmental disorders.

Chronic epilepsy has been associated with hippocampal abnormalities like neuronal loss, gliosis and granule cell dispersion. The granule cell layer of a normal human hippocampal dentate gyrus is traditionally regarded as a compact neuron-dense layer. Histopathological studies of surgically resected or autopsied hippocampal samples primarily from temporal lobe epilepsy patients, as well as animal models of epilepsy, describe variable patterns of granule cell dispersion including focal cell clusters, broader thick segments, and bilamination or "tram-tracking". Although most studies have implicated granule cell dispersion as a specific feature of chronic epilepsy, very few "non-seizure" controls were included in these published investigations. Our retrospective survey of 147 cadaveric pediatric human hippocampi identified identical morphological spectra of granule cell dispersion in both normal and seizure-affected brains. Moreover, sections across the entire antero-posterior axis of a control cadaveric hippocampus revealed repetitive occurrence of different morphologies of the granule cell layercompact, focally disaggregated and bilaminar. The results indicate that granule cell dispersion is within the spectrum of normal variation and not unique to patients with epilepsy. We speculate that sampling bias has been responsible for an erroneous dogma, which we hope to rectify with this investigation.