Timing neurogenesis and differentiation: insights from quantitative clonal analyses of cerebellar granule cells. J Neurosci

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: 6.75). 04/2008; 28(10):2301-12. DOI: 10.1523/JNEUROSCI.5157-07.2008
Source: PubMed

ABSTRACT 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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    • "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. "
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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.
    Development 11/2014; 141(21):4031-4041. DOI:10.1242/dev.106559 · 6.27 Impact Factor
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    • "The lack of colonization of the IGL by mutant cells stands in stark contrast to the more extensive colonization in EGL described above. In wildtype chimeras or mosaic cerebella, there is a generally one-to-one correspondence in the proportion of EGL cells to IGL cells with relation to the genotype in wildtype chimeras (Espinosa and Luo, 2008; Ryder and Cepko, 1994; Swanson and Goldowitz, unpublished results). This radial relationship between EGL and IGL, however, is not seen in P10 mutant chimeras. "
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    ABSTRACT: Pax6 has been implicated in cerebellar granule cell development, however the neonatal lethality of the Sey/Sey mutant has precluded a more detailed study of this late developing neuronal type. In this study we use experimental mouse chimeras made from wildtype and Pax6-null embryos to circumvent early lethality and assess the developmental potential of mutant cells in the construction of the cerebellum. We have identified the granule cell as a direct target of mutant gene action, with glia and Purkinje cells being affected in what is largely a non-cell autonomous manner. Most dramatically, in postnatal day 21 (P21) chimeras, mutant cells are largely absent in the anterior and posterior cerebellum while present in central lobules, but amidst disorganized cerebellar architecture. Analysis of P0/1 and P10 chimeras demonstrates a profound temporally based defect where mutant cells colonize the anterior and posterior EGL but fail to migrate to the IGL. Mutant granule cells in the central lobules can reach the IGL in an abnormal manner, with large streams of cells forming raphes through the molecular layer. These studies provide new insights into the role of Pax6 in postnatal cerebellar development that pinpoint the granule cell as an intrinsic target of the mutant gene and key events in the life of the developing granule cell that depend upon normal Pax6 expression.
    Developmental Biology 03/2011; 351(1):1-12. DOI:10.1016/j.ydbio.2010.11.018 · 3.64 Impact Factor
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