Deconstructing cerebellar development cell by cell

Abstract

The cerebellum is a pivotal centre for the integration and processing of motor and sensory information. Its extended development into the postnatal period makes this structure vulnerable to a variety of pathologies, including neoplasia. These properties have prompted intensive investigations that reveal not only developmental mechanisms in common with other regions of the neuraxis but also unique strategies to generate neuronal diversity. How the phenotypically distinct cell types of the cerebellum emerge rests on understanding how gene expression differences arise in a spatially and temporally coordinated manner from initially homogeneous cell populations. Increasingly sophisticated fate mapping approaches, culminating in genetic-induced fate mapping, have furthered the understanding of lineage relationships between early-versus later-born cells. Tracing the developmental histories of cells in this way coupled with analysis of gene expression patterns has provided insight into the developmental genetic programmes that instruct cellular heterogeneity. A limitation to date has been the bulk analysis of cells, which blurs lineage relationships and obscures gene expression differences between cells that underpin the cellular taxonomy of the cerebellum. This review emphasises recent discoveries, focusing mainly on single-cell sequencing in mouse and parallel human studies that elucidate neural progenitor developmental trajectories with unprecedented resolution. Complementary functional studies of neural repair after cerebellar injury are challenging assumptions about the stability of postnatal cellular identities. The result is a wealth of new information about the developmental mechanisms that generate cerebellar neural diversity, with implications for human evolution.

A Focus on the Cerebellum: From Embryogenesis to an Age-Related Clinical Perspective

“…To better perceive the cerebellar functions’ complexity, it is crucial to understand its morphogenesis and how its connections with other CNS structures are established. Cerebellar development is a process that starts early during the first trimester of pregnancy (30 days post- conception) and lasts until 2 years of postnatal age ( van Essen et al, 2020 ). There are very few literature data regarding human cerebellar development before the 8th gestational week ( Haldipur et al, 2018 ) and most of our knowledge about cellular and molecular maturation is derived from animal-based studies on fish, birds and rodents, especially mice.…”

As above, so below: Whole transcriptome profiling supports the continuum hypothesis of avian dorsal and ventral pallium organization

“…Investigating the open regulatory regions in the continuous cell populations using ATAC-Seq would offer insights into the regulatory landscape of the cell types within these populations and if they are activating the same expression networks via convergent or homologous means. Systematic lineage tracing experiments, paired with in situs for the shared expression markers found in this study, would provide evidence to test competing hypotheses on the developmental origins of similar subdivisions (Solek and Ekker, 2012; Montiel et al ., 2016; van Essen et al ., 2020).…”

In Search of Molecular Markers for Cerebellar Neurons

“…Several studies have adopted this approach in searching for neuronal markers in the cerebellum [ 20 , 94 , 95 , 96 , 97 ]. For example, single-cell RNA-seq is performed to study the gene expression of the developing cerebellum at eight prenatal time points (daily sampling at E10 to E17) and four postnatal time points (P0, P4, P7, P10) [ 94 ].…”

“…Two germinative zones are established in the cerebellar primordium: the ventricular zone and the rhombic lip. Whereas PCs and other GABAergic interneurons (e.g., Golgi cells, globular cells, Lugaro cells, basket cells, stellate cells, and candelabrum cells) are derived from the ventricular zone, GCs—the most abundant neurons in the cerebellum—and another type of glutamatergic interneuron unipolar brush cell are derived from the rhombic lip [ 13 , 19 , 20 ]. From E10.5 onward, postmitotic PCs emigrate from the ventricular zone, migrating toward the pial surface, where the PCs colonize, differentiate, and give rise to the PC layers of the cerebellum [ 17 ].…”