Abstract
For neural systems to function effectively, the numbers of each cell type must be proportioned properly during development. We found that conditional knockout of the mouse homeobox genes En1 and En2 in the excitatory cerebellar nuclei neurons (eCN) leads to reduced postnatal growth of the cerebellar cortex. A subset of medial and intermediate eCN are lost in the mutants, with an associated cell non-autonomous loss of their presynaptic partner Purkinje cells by birth leading to proportional scaling down of neuron production in the postnatal cerebellar cortex. Genetic killing of embryonic eCN throughout the cerebellum also leads to loss of Purkinje cells and reduced postnatal growth but throughout the cerebellar cortex. Thus, the eCN play a key role in scaling the size of the cerebellum by influencing the survival of their Purkinje cell partners, which in turn regulate production of granule cells and interneurons via the amount of sonic hedgehog secreted.
Highlights
A key aspect of brain development is the production of the numerous cell types in the correct proportions so they can assemble into nascent networks
When the vermis and paravermis were divided into three regions - an anterior sector (ASec), anterior to the primary fissure; a central sector (CSec), between the primary and secondary fissures; and a posterior sector (PSec), posterior to the secondary fissure, the PSec had no significant reduction, whereas the ASec and CSec were significantly decreased in area in Atoh1-Engrailed 1 and 2 (En1/2) CKOs compared to littermate controls (ASec and CSec of the midline: 37.1 ± 3.6% and 55.4 ± 2.7%; paravermis: 25.0 ± 1.4% and 46.7 ± 7.0%) (Figure 1H, Figure 1—figure supplement 1A)
The results of our study show that if the number of Purkinje cells (PCs) is reduced around birth, the other neurons generated postnatally in the cerebellar cortex are scaled back in numbers to be proportional to the number of PCs, and producing a normally proportioned cytoarchitecture (Figure 9)
Summary
A key aspect of brain development is the production of the numerous cell types in the correct proportions so they can assemble into nascent networks. The number of cells produced is scaled down based on survival factors produced by target neurons (neurotrophic theory; Cowan et al, 1984; Levi-Montalcini and Hamburger, 1951; Oppenheim, 1991; Snider, 1994). The cerebellum represents a powerful system in which to study the phenomenon of cell number scaling during development, since by birth the specification of neuronal lineages is complete but neurogenesis of several cell types has just begun. The folds (lobules) are considered the cerebellar cortex, and they overlay the cerebellar nuclei (CN), two bilaterally symmetrical groups of mediolaterally-arrayed nuclei in mice (medial, intermediate and lateral nuclei), that house the main output neurons of the cerebellum (Sillitoe and Joyner, 2007).
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