Abstract
Development of the cerebellum proceeds under the precise spatio-temporal control of several key developmental signalling pathways, including the Wnt/β-catenin pathway. We recently reported the activity of Wnt/β-catenin signalling in the perinatal cerebellar ventricular zone (VZ), a germinal centre in the developing cerebellum that gives rise to GABAergic and glial cells. In order to investigate the normal function of Wnt/β-catenin signalling in the VZ and the cell lineages it gives rise to, we used a combination of ex vivo cerebellar slice culture and in vivo genetic manipulation to dysregulate its activity during late embryonic development. Activation of the pathway at the cerebellar ventricular zone led to a reduction in the number of cells expressing the glial lineage markers Sox9 and GFAP and the interneuron marker Pax2, but had no consistent effect on either proliferation or apoptosis. Our findings suggest that activation of the Wnt/β-catenin pathway in the cerebellar ventricular zone causes a shift in the cell types produced, most likely due to disruption of normal differentiation. Thus, we propose that regulation of Wnt/β-catenin signalling levels are required for normal development of cells arising from the cerebellar ventricular zone during late embryogenesis.
Highlights
The adult cerebellum contains a variety of types of neurons and glia, arranged in a highly characteristic laminar structure
From E12.5, the upper rhombic lip (URL) gives rise to granule progenitor cells (GPCs) which stream across the pial surface of the cerebellum to form the external granule layer (EGL)
Activation of Wnt/b-catenin signalling led to a marked decrease in the production of both Sox9+ and Pax2+ cell lineages – key markers of glia and interneurons respectively. This decrease did not correlate with consistent changes in proliferation or cell death and we propose a potential role for Wnt/b-catenin signalling in regulating differentiation at the cerebellar ventricular zone
Summary
The adult cerebellum contains a variety of types of neurons and glia, arranged in a highly characteristic laminar structure. PCs, GCs and Bergmann glia all extend processes into the cell-sparse molecular layer (ML), which contains a further population of interneurons (reviewed in [1,2]). Glutamatergic DCN neurons are specified first, from E10.5 These migrate rostrally from the URL, across the dorsal surface of the cerebellum. From E12.5, the URL gives rise to granule progenitor cells (GPCs) which stream across the pial surface of the cerebellum to form the external granule layer (EGL). The GPCs in the EGL proliferate extensively from around E18.5, continuing into the first two postnatal weeks Following their terminal mitosis, GCs migrate inwards through the PCL to reside in the IGL – a process that is largely complete by P21 [2]
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