Timing Neurogenesis and Differentiation: Insights from Quantitative Clonal Analyses of Cerebellar Granule Cells

Howard Hughes Medical Institute and Department of Biology, Neurosciences Program, Stanford University, Stanford, California 94305, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 04/2008; 28(10):2301-12. DOI: 10.1523/JNEUROSCI.5157-07.2008
Source: PubMed


The cerebellum is an excellent model system to study how developmental programs give rise to exquisite neuronal circuits in the adult brain. Here, we describe our findings regarding granule cell neurogenesis and differentiation using the MADM method (mosaic analysis with double markers) in mice. By following the development of individual granule cell clones, we show that (1) granule cell precursors (GCPs) undergo predominantly symmetric division during postnatal development; (2) clonally related granule cells (GCs) exit the cell cycle within a narrow time window and stack their axons in the molecular layer in chronological order from deep to superficial sublayers; and (3) whereas the average GCP proliferation in the external granular layer is progressively slower as development proceeds, there is a rapid expansion of GCPs shortly before clonally related GCs exit the cell cycle. These properties produce GC clones that are distinct, each having a restricted axonal projection, but that are on average similar in cell number. We discuss possible developmental mechanisms and functional implications of these findings.

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    • "We did not address whether cells in which β-Catenin dividing symmetrically were confined to particular layers of the EGL since the characteristic of the EGL is continually changing during the first two postnatal weeks, for example the thickness of the PCNA positive or the NeuroD1 positive layers (supplementary material Fig. S2A-C). However, a study by Espinosa and Luo (Espinosa and Luo, 2008) showed that GCP divide symmetrically postnatally and GCP's that exit the cell cycle at around the same time are clonal. Whether this relates to β-Catenin distribution remains to be seen. "
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    ABSTRACT: Granule neuron progenitors (GNPs) plane of cell division was analysed with respect to the pial surface in P0 to P14 cerebellum and the results showed that there was a significant bias towards the plane of cell division being parallel to pial surface across this developmental window. In addition, the distribution of β-Catenin in anaphase cells was analysed, which showed that there was a significant asymmetry in the distribution of β-Catenin in dividing GNPs. Further, inhibition of Sonic Hedgehog (Shh) signalling had an effect on plane of cell division. Asymmetric distribution of β-Catenin is shown to occur towards the source of a localized extracellular cue. © 2015. Published by The Company of Biologists Ltd.
    Full-text · Article · May 2015 · Biology Open
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    • "In the rat most granule cells are formed during the second postnatal week, but due to the time required for their migration and the formation of dendrites , few glomerular synapses are formed with mossy fibers before the beginning of the third postnatal week (Altman, 1972). In the mouse, a similar pattern, but with somewhat faster dynamics is observed (Espinosa and Luo, 2008). Therefore, the developmental increase in total DNA recombination (Fig. 1 B) must be interpreted as recombination in GCs newly arriving in the IGL over a protracted period of time rather than as a delayed recombination of DNA in a constant number of GCs during the time of synapse formation. "

    Full-text · Article · Feb 2015
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    • "The factors governing how individual progenitors navigate this environment and terminate transit amplification are less clear and yet equally important in development and disease. The lack of an internal cell division clock (Espinosa and Luo, 2008) has focussed attention on cell non-autonomous factors such Wnt and bone morphogenetic protein (BMP) pathway signals in the EGL. For example, non-canonical Wnt signalling via Wnt3 has recently been shown to be capable of decreasing proliferation independently of BMP signalling (Anne et al., 2013). "
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    ABSTRACT: The cerebellum is a pre-eminent model for the study of neurogenesis and circuit assembly. Increasing interest in the cerebellum as a participant in higher cognitive processes and as a locus for a range of disorders and diseases make this simple yet elusive structure an important model in a number of fields. In recent years, our understanding of some of the more familiar aspects of cerebellar growth, such as its territorial allocation and the origin of its various cell types, has undergone major recalibration. Furthermore, owing to its stereotyped circuitry across a range of species, insights from a variety of species have contributed to an increasingly rich picture of how this system develops. Here, we review these recent advances and explore three distinct aspects of cerebellar development - allocation of the cerebellar anlage, the significance of transit amplification and the generation of neuronal diversity - each defined by distinct regulatory mechanisms and each with special significance for health and disease.
    Full-text · Article · Nov 2014 · Development
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