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

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.

• Publication year

  2008

• Venue

  Journal of Neuroscience

• Publication date

  2008-03-05

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1523/JNEUROSCI.5157-07.2008PMID 18322077PMCID PMC2586640
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Patched 1 Regulates Hedgehog Signaling at the Primary Cilium

  2007cited by this paper
• Morphology, molecular codes, and circuitry produce the three-dimensional complexity of the cerebellum.

  2007cited by this paper
• Patched1 Regulates Hedgehog Signaling at the Primary Cilium

  2007cited by this paper
• A Crucial Role for p57Kip2 in the Intracellular Timer that Controls Oligodendrocyte Differentiation

  2007cited by this paper
• Modeling sporadic loss of heterozygosity in mice by using mosaic analysis with double markers (MADM)

  2007cited by this paper
• Stem cell proliferative history in tissue revealed by temporal halogenated thymidine analog discrimination

  2005influential reference
• Speed limits in the cerebellum: constraints from myelinated and unmyelinated parallel fibers

  2005cited by this paper
• Math1 expression redefines the rhombic lip derivatives and reveals novel lineages within the brainstem and cerebellum.

  2005cited by this paper
• Math1 is expressed in temporally discrete pools of cerebellar rhombic-lip neural progenitors.

  2005cited by this paper
• Morphogenetic and cellular movements that shape the mouse cerebellum; insights from genetic fate mapping.

  2005cited by this paper
• Mosaic analysis with double markers in mice.

  2005cited by this paper
• Sonic hedgehog signaling is required for expansion of granule neuron precursors and patterning of the mouse cerebellum.

  2004cited by this paper
• Progressive restriction of cell fates in relation to neuroepithelial cell mingling in the mouse cerebellum.

  2003cited by this paper
• Emerging rules for the distributions of active dendritic conductances

  2002cited by this paper
• Mice that lack astrotactin have slowed neuronal migration.

  2002cited by this paper
• Efficient recombination in diverse tissues by a tamoxifen-inducible form of Cre: a tool for temporally regulated gene activation/inactivation in the mouse.

  2002cited by this paper
• A cre recombinase transgene with mosaic, widespread tamoxifen‐inducible action

  2002cited by this paper
• Inhibition of Cyclin E–Cyclin-Dependent Kinase 2 Complex Formation and Activity Is Associated with Cell Cycle Arrest and Withdrawal in Oligodendrocyte Progenitor Cells

  2001cited by this paper
• Site- and time-specific gene targeting in the mouse.

  2001cited by this paper
• Genetic regulation of cerebellar development

  2001cited by this paper
• Control of neuronal precursor proliferation in the cerebellum by Sonic Hedgehog.

  1999cited by this paper
• The mathematics of neocortical neuronogenesis.

  1997cited by this paper
• Histology of the Nervous System of Man and Vertebrates

  1997cited by this paper
• The compartmentalization of the cerebellum.

  1997cited by this paper
• Embryonic precursor cells from the rhombic lip are specified to a cerebellar granule neuron identity.

  1996cited by this paper
• Biochemical evidence that Patched is the Hedgehog receptor

  1996cited by this paper
• Asymmetric localization of a mammalian numb homolog during mouse cortical neurogenesis.

  1996cited by this paper
• Developmental fates and migratory pathways of dividing progenitors in the postnatal rat cerebellum

  1996cited by this paper
• Development of the Cerebellar System: In Relation to Its Evolution, Structure, and Functions

  1996influential reference
• Conservation of the hedgehog/patched signaling pathway from flies to mice: induction of a mouse patched gene by Hedgehog.

  1996cited by this paper
• Mechanisms of neural patterning and specification in the developing cerebellum.

  1995cited by this paper
• Proliferative events in the cerebral ventricular zone.

  1995cited by this paper
• The cell cycle of the pseudostratified ventricular epithelium of the embryonic murine cerebral wall

  1995cited by this paper
• Survival and differentiation of adult neuronal progenitor cells transplanted to the adult brain.

  1995influential reference
• Cleavage orientation and the asymmetric inheritance of Notch1 immunoreactivity in mammalian neurogenesis.

  1995cited by this paper
• Evidence for large-scale astrocyte death in the developing cerebellum

  1995influential reference
• Migration patterns of clonally related granule cells and their progenitors in the developing chick cerebellum.

  1994cited by this paper
• A novel role for thyroid hormone, glucocorticoids and retinoic acid in timing oligodendrocyte development.

  1994influential reference
• Ontogeny of afferents to the fetal rat cerebellum.

  1992cited by this paper
• BUdR as an S-phase marker for quantitative studies of cytokinetic behaviour in the murine cerebral ventricular zone

  1992cited by this paper
• Quantitatives studies on the mammalian cerebellum

  1991cited by this paper
• Origin of cuneate projections to the anterior and posterior lobes of the rat cerebellum.

  1991cited by this paper
• Origin of spinal projections to the anterior and posterior lobes of the rat cerebellum

  1991cited by this paper
• A new approach to the development of the cerebellum provided by the quail-chick marker system.

  1990cited by this paper
• Development and death of external granular layer cells in the weaver mouse cerebellum: a quantitative study

  1989cited by this paper
• PDGF receptors on cells of the oligodendrocyte-type-2 astrocyte (O-2A) cell lineage.

  1989cited by this paper
• Clonal analysis of oligodendrocyte development in culture: evidence for a developmental clock that counts cell divisions.

  1986cited by this paper
• Changes in cell proliferation kinetics in the mouse cerebellum after total asphyxia.

  1985cited by this paper
• Thyroid hormone effects on growth and development

  1985cited by this paper
• The modifiable neuronal network of the cerebellum.

  1984cited by this paper
• Direct correlation between Purkinje and granule cell number in the cerebella of lurcher chimeras and wild-type mice.

  1983cited by this paper
• Congruence of spatial organization of tactile projections to granule cell and Purkinje cell layers of cerebellar hemispheres of the albino rat: vertical organization of cerebellar cortex.

  1983cited by this paper
• Cell death in the external granular layer of normal and undernourished rats: further observations, including estimates of rate of cell loss.

  1983influential reference
• Do cells cycle?

  1973cited by this paper
• Neuron‐glia relationship during granule cell migration in developing cerebellar cortex. A Golgi and electonmicroscopic study in Macacus rhesus

  1971cited by this paper
• Neurogenesis and morphogenesis in the cerebellar cortex.

  1970cited by this paper
• The cellular kinetics of the developing mouse cerebellum. I. The generation cycle, growth fraction and rate of proliferation of the external granular layer.

  1970cited by this paper
• Types and distribution of synapses upon basket and stellate cells of the mouse cerebellum: An electron microscopic study

  1968cited by this paper
• Regulation of cell reproduction.

  1968cited by this paper
• Formation and differentiation of the external granular layer of the chick cerebellum

  1967cited by this paper
• Significance of Mitotic Spindle Fibre Orientation in the Neural Tube

  1967cited by this paper
• QUANTITATIVE ANALYSIS OF CELL PROLIFERATION AND DIFFERENTIATION IN THE CORTEX OF THE POSTNATAL MOUSE CEREBELLUM

  1967influential reference
• Behavior of neuro‐epithelial cells during closure of the neural tube

  1966cited by this paper
• EVIDENCE FOR AN ESSENTIALLY CONSTANT DURATION OF DNA SYNTHESIS IN RENEWING EPITHELIA OF THE ADULT MOUSE

  1963cited by this paper
• An autoradiographic analysis of histogenesis in the mouse cerebellum.

  1961cited by this paper
• A quantitative study of the Purkinje cell dendritic branchlets and their relationship to afferent fibres.

  1957cited by this paper

• Hierarchical regulation of cerebellar neurogenesis by Sin3A-mediated gene repression

  2025cites this paper
• CHLOK: a chemigenetic multicolor labeling system to visualize neuronal birthdate and circuit integration

  2025cites this paper
• Ignoring the cerebellum is hindering progress in neuroscience.

  2025cites this paper
• Developmental Connectomics of the Mouse Cerebellum

  2025cites this paper
• G-quadruplexes are a source of vulnerability in BRCA2 deficient granule cell progenitors and medulloblastoma

  2024cites this paper
• Permanent deconstruction of intracellular primary cilia in differentiating granule cell neurons

  2024cites this paper
• Cytomegalovirus infection lengthens the cell cycle of granule cell precursors during postnatal cerebellar development

  2024influential citation
• Cell division angle predicts the level of tissue mechanics that tune the amount of cerebellar folding

  2024cites this paper
• Ezh2 Delays Activation of Differentiation Genes During Normal Cerebellar Granule Neuron Development and in Medulloblastoma

  2024cites this paper
• Postnatal zinc deficiency due to giardiasis disrupts hippocampal and cerebellar development

  2024cites this paper
• Becker Digital Commons

  2023cites this paper
• A genetic mosaic mouse model illuminates the pre-malignant progression of basal-like breast cancer

  2023cites this paper
• Developmental timing-dependent organization of synaptic connections between mossy fibers and granule cells in the cerebellum

  2023cites this paper
• Bromodomain and Extra-Terminal Proteins in Brain Physiology and Pathology: BET-ing on Epigenetic Regulation

  2023cites this paper
• 3D reconstruction of the cerebellar germinal layer reveals tunneling connections between developing granule cells

  2023cites this paper
• Histone bivalency regulates the timing of cerebellar granule cell development

  2023cites this paper
• Wdr4 promotes cerebellar development and locomotion through Arhgap17-mediated Rac1 activation

  2023cites this paper
• Automated Immunofluorescence Staining for Analysis of Mitotic Stages and Division Orientation in Brain Sections.

  2023cites this paper
• TRANSCRIPTION FACTORS IN CEREBELLAR DEVELOPMENT

  2023cites this paper
• Permanent deconstruction of intracellular primary cilia in differentiating granule cell neurons

  2023cites this paper
• Single-cell epigenomics and spatiotemporal transcriptomics reveal human cerebellar development

  2023cites this paper
• A genetic mosaic mouse model illuminates the pre-malignant progression of basal-like breast cancer

  2023influential citation
• Targeted approaches to delineate neuronal morphology during early development

  2023cites this paper
• Utilizing Cre-lox-based mouse genetic tools in neuroscience research

  2023cites this paper
• Galnt17 loss-of-function leads to developmental delay and abnormal coordination, activity, and social interactions with cerebellar vermis pathology.

  2022cites this paper
• Multicolor strategies for investigating clonal expansion and tissue plasticity

  2022cites this paper
• Deletion of CHD8 in cerebellar granule neuron progenitors leads to severe cerebellar hypoplasia, ataxia and psychiatric behavior in mice.

  2022cites this paper
• Neuronal Polarity Pathways as Central Integrators of Cell-Extrinsic Information During Interactions of Neural Progenitors With Germinal Niches

  2022cites this paper
• Cytomegalovirus infection in newborn mice alters cerebellar development by lengthening G1/S phases of cerebellar granule cell precursors during postnatal cerebellar development

  2022cites this paper
• Cerebellum lineage allocation, morphogenesis and repair: impact of interplay amongst cells.

  2022cites this paper
• 3D reconstruction of the cerebellar germinal layer reveals intercytoplasmic connections between developing granule cells

  2022cites this paper
• The Conflicting Role of Caffeine Supplementation on Hyperoxia-Induced Injury on the Cerebellar Granular Cell Neurogenesis of Newborn Rats

  2022cites this paper
• Performing Single-Cell Clonal Analysis in the Mouse Brain Using Mosaic Analysis with Double Markers (MADM).

  2022cites this paper
• Computation, wiring, and plasticity in synaptic clusters.

  2021cites this paper
• Pleiotropic effects of BDNF on the cerebellum and hippocampus: Implications for neurodevelopmental disorders.

  2021cites this paper
• A matter of space and time: Emerging roles of disease-associated proteins in neural development.

  2021cites this paper
• Advanced Technologies for Local Neural Circuits in the Cerebral Cortex

  2021cites this paper
• CEP120-mediated KIAA0753 recruitment onto centrioles is required for timely neuronal differentiation and germinal zone exit in the developing cerebellum

  2021cites this paper
• Ccdc134 deficiency impairs cerebellar development and motor coordination

  2021cites this paper
• The Effects of MAPK Signaling on the Development of Cerebellar Granule Cells

  2021cites this paper
• Utilizing In Vivo Postnatal Electroporation to Study Cerebellar Granule Neuron Morphology and Synapse Development.

  2021cites this paper
• Plexin-B2 controls the timing of differentiation and the motility of cerebellar granule neurons

  2021cites this paper
• Projection-dependent heterogeneity of cerebellar granule cell calcium responses

  2021cites this paper
• Reduced Granule Cell Proliferation and Molecular Dysregulation in the Cerebellum of Lysosomal Acid Phosphatase 2 (ACP2) Mutant Mice

  2021cites this paper
• The relationship between birth timing, circuit wiring, and physiological response properties of cerebellar granule cells

  2021influential citation
• The regulatory landscape of cells in the developing mouse cerebellum

  2021cites this paper
• Emerging Role of Long Noncoding RNAs in Perioperative Neurocognitive Disorders and Anesthetic-Induced Developmental Neurotoxicity

  2020cites this paper
• Generation of excitatory and inhibitory neurons from common progenitors via Notch signaling in the cerebellum

  2020cites this paper
• BMP signalling facilitates transit amplification in the developing chick and human cerebellum

  2020cites this paper
• Type II interferon signaling in the brain during a viral infection with age‐dependent pathogenesis

  2020cites this paper
• Research progress and treatment strategies for anesthetic neurotoxicity.

  2020cites this paper
• Mosaic Analysis with Double Markers reveals IGF1R function in granule cell progenitors during cerebellar development.

  2020cites this paper
• A boy with a congenital cerebellar mass

  2020cites this paper
• GluD2- and Cbln1-mediated Competitive Synaptogenesis Shapes the Dendritic Arbors of Cerebellar Purkinje Cells

  2020cites this paper
• Interactions between Purkinje cells and granule cells coordinate the development of functional cerebellar circuits.

  2020cites this paper
• Neurogenesis in the cerebellum

  2020cites this paper
• Gradients in the mammalian cerebellar cortex enable Fourier-like transformation and improve storing capacity

  2020cites this paper
• Suppressor of fused controls cerebellum granule cell proliferation by suppressing Fgf8 and spatially regulating Gli proteins

  2020cites this paper
• A Genome-wide Library of MADM Mice for Single-Cell Genetic Mosaic Analysis

  2020cites this paper
• Shh-Mediated Increase in β-Catenin Levels Maintains Cerebellar Granule Neuron Progenitors in Proliferation

  2020cites this paper
• Lineage Tracing and Clonal Analysis in Developing Cerebral Cortex Using Mosaic Analysis with Double Markers (MADM).

  2020cites this paper
• Neuronal and glial regulation of CNS angiogenesis and barriergenesis

  2020cites this paper
• GluD2- and Cbln1-mediated competitive interactions shape the dendritic arbors of cerebellar Purkinje cells.

  2020cites this paper
• ANALYSIS OF GRANULE CELL GENERATION SYSTEM BY LIE SYMMETRY METHOD

  2020cites this paper
• Gradients in the cerebellar cortex enable Fourier-like transformation and improve storing capacity

  2019cites this paper
• Brd4 Is Required for Granule Cell Progenitor Proliferation

  2019cites this paper
• The interplay between TGF‐β‐stimulated TSC22 domain family proteins regulates cell‐cycle dynamics in medulloblastoma cells

  2019cites this paper
• The Cre/Lox System to Assess the Development of the Mouse Brain.

  2019cites this paper
• Trim32 suppresses cerebellar development and tumorigenesis by degrading Gli1/sonic hedgehog signaling

  2019cites this paper
• Inputs from Sequentially Developed Parallel Fibers Are Required for Cerebellar Organization.

  2019cites this paper
• A non-canonical role for p27Kip1 in restricting proliferation of corneal endothelial cells during development

  2019cites this paper
• Foxr2 promotes formation of CNS-embryonal tumors in a Trp53-deficient background.

  2019cites this paper
• Signaling pathways in cerebellar granule cells development.

  2019cites this paper
• Microglia in the juvenile brain after cranial irradiation

  2019cites this paper
• Deletion of the α subunit of the heterotrimeric Go protein impairs cerebellar cortical development in mice

  2019influential citation
• Sensorimotor Coding of Vermal Granule Neurons in the Developing Mammalian Cerebellum

  2019influential citation
• Specification of Granule Cells and Purkinje Cells

  2019cites this paper
• Insights into cerebellar development and connectivity.

  2019cites this paper
• Short-term plasticity at cerebellar granule cell to molecular layer interneuron synapses expands information processing

  2019cites this paper
• The generation of granule cells during the development and evolution of the cerebellum

  2019cites this paper
• Adaptive effects of gestational caloric restriction in the mitochondria of Wistar rats' brain: A DOHaD approach

  2019cites this paper
• Time series modeling of cell cycle exit identifies Brd4 dependent regulation of cerebellar neurogenesis

  2019cites this paper
• Region-specific changes in Mus musculus brain size and cell composition under chronic nutrient restriction

  2019cites this paper
• Persistent motor dysfunction despite homeostatic rescue of cerebellar morphogenesis in the Car8 waddles mutant mouse

  2019cites this paper
• Developmental phosphoproteomics identifies the kinase CK2 as a driver of Hedgehog signaling and a therapeutic target in medulloblastoma

  2018cites this paper
• Neural lineage tracing in the mammalian brain.

  2018cites this paper
• Linking neuronal lineage and wiring specificity

  2018cites this paper
• Meis1 Coordinates Cerebellar Granule Cell Development by Regulating Pax6 Transcription, BMP Signaling and Atoh1 Degradation

  2018cites this paper
• Creating Lineage Trajectory Maps Via Integration of Single‐Cell RNA‐Sequencing and Lineage Tracing

  2018cites this paper
• Recent advances in understanding the mechanisms of cerebellar granule cell development and function and their contribution to behavior

  2018cites this paper
• The RNA-binding protein LIN28 controls progenitor and neuronal cell fate during postnatal neurogenesis

  2018cites this paper
• The Transcriptional Regulator SnoN Promotes the Proliferation of Cerebellar Granule Neuron Precursors in the Postnatal Mouse Brain

  2018cites this paper
• Chronology-based architecture of descending circuits that underlie the development of locomotor repertoire after birth

  2018cites this paper
• Molecular and functional heterogeneity of cerebellar granule cell terminals expands temporal coding in molecular layer interneurons

  2018cites this paper
• Physiopathologie des déficits moteurs dans les troubles du spectre autistique : approche neuroanatomique dans deux modèles environnementaux

  2018cites this paper
• Mechanisms of radial glia progenitor cell lineage progression

  2017cites this paper
• Specific Temporal Distribution and Subcellular Localization of a Functional Vesicular Nucleotide Transporter (VNUT) in Cerebellar Granule Neurons

  2017cites this paper
• Pretreatment with minocycline restores neurogenesis in the subventricular zone and subgranular zone of the hippocampus after ketamine exposure in neonatal rats.

  2017cites this paper
• Cellular and Genetic Programs Underlying Cerebellum Development

  2017cites this paper
• The Syk kinases orchestrate cerebellar granule cell tangential migration.

  2017cites this paper