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WIREs Dev Biol
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Development of the cerebellum: from gene expression patterns to circuit maps

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Abstract The internal structure of the cerebellum reflects an intriguing paradox; its cytoarchitecture is relatively simple and repeated throughout, yet the connections between its neurons are wired into a complex array of gene expression domains and functional circuits. The developmental mechanisms that coordinate the establishment of cerebellar structure and circuitry provide a powerful model for understanding how functional brain networks are formed. Two primary germinal zones generate the cells that make up the cerebellum. Each zone expresses a specific set of genes that establish the cell lineages within the cerebellar anlage. Then, cohorts of differentiated projection neurons and interneuron progenitors migrate into the developing cerebellum. Thereafter, a number of remarkable patterning events occur including transformation of the smooth cerebellar surface into an intricately patterned series of folds, formation of three distinct cellular layers, and the demarcation of parasagittal gene expression domains. Together, these structural and molecular organizations are thought to support the proper connectivity between incoming afferent projections and their target cells. After birth, genetic programs and neural activity repattern synaptic connections into topographic neural networks called modules, which are organized around a longitudinal zone plan and are defined by their molecular, anatomic, and functional properties. WIREs Dev Biol 2013, 2:149–164. doi: 10.1002/wdev.65 This article is categorized under: Nervous System Development > Vertebrates: Regional Development

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(a) The adult cerebellum, shown here as a whole mount viewed dorsally, is anatomically divided along the mediolateral axis into three major regions: vermis, paravermis, and hemispheres. Most laterally are the paraflocculi and flocculi. Conserved foliation patterns divide the cerebellum into 10 lobules, typically identified with Roman numerals. Abbreviations: LS, lobulus simplex; PML, paramedian lobule; COP, copula pyramidis (a, anterior; p, posterior). (b) A sagittal section of the cerebellar vermis revealing the stereotypical foliation pattern, which consists of 10 lobules. The four transverse domains have been identified with separate colors. The hemispheres have a distinct foliation pattern compared with the vermis (not shown7).

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(a) A dorsal view of the cerebellum at embryonic day 12 (E12). The cerebellum is outlined with a white line. The black dotted line represents the sagittal section shown in panel (b). Abbreviations: Mb, midbrain; Cb, cerebellum; Bs, brainstem (a, anterior; p, posterior). (b) The cerebellar primordium consists of two germinal zones. The ventricular zone (green) and the rhombic lip (pink) generate GABAergic and glutamatergic neurons, respectively. The migratory pathways from each zone are represented with arrows. Neurons born in the ventricular zone migrate radially into the interior of the cerebellar primordium (blue). In contrast, rhombic lip‐derived cells (yellow) exhibit an initial tangential migration (single‐curved black arrow) followed by radial migration (two arrows). Abbreviations: VZ, ventricular zone; RL, rhombic lip (a, anterior; p, posterior; d, dorsal; v, ventral).

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Gene expression patterns define subsets of Purkinje cells at all stages of cerebellar development. The two whole mounts shown in this image are seen from a dorsal view. As early as embryonic day 15 (E15), and before Purkinje cells have formed a monolayer, calbindin (CALB1) expression reveals a distinct pattern of embryonic ‘clusters’ (outlined in black and indicated by asterisks). In the adult cerebellum aldolase C (ALDOC) expression, which is revealed by zebrinII antibody staining, delineates stripes of Purkinje cells (e.g., those indicated with arrowheads). Roman numerals indicate the lobules (as in Figure 1), while Arabic numerals identify ALDOC stripes (for nomenclature see Ref 21). For simplicity, we have only labeled ALDOC positive stripes in lobule VIII of the vermis and in Crus II of the hemispheres. The basic pattern of lobules and the configuration of ALDOC stripes are highly conserved between individuals and across species. Abbreviations: m, midline; LS, lobulus simplex; PML, paramedian lobule; COP, copula pyramids.

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The circuitry of the cerebellum is well understood. In this simplified schematic, we illustrate that climbing fibers (CFs) originate exclusively from neurons in the inferior olivary nuclei (ION). In contrast, mossy fibers (MFs) originate from a large number of precerebellar nuclei (PN). CFs terminate upon neurons in the cerebellar nuclei (fn, fastigial nucleus; in, interpositus nucleus; dn, dentate nucleus) and on Purkinje cell dendrites. MFs terminate on neurons in the cerebellar nuclei, on granule cell dendrites, and on unipolar brush cells. Distinct types of interneurons reside in each of the three layers and make specific connection within the cerebellar cortex. Efferent projections of the cerebellar cortex (Purkinje cell axons) and of the cerebellum (cerebellar nuclei axons) are topographically organized. Layers of the cerebellum: molecular layer (ml), Purkinje cell layer (pcl), granular layer (gl), white matter (wm), cerebellar nuclei (cn).

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(a) A simplified timeline depicting the major steps of mouse cerebellar development and their respective time‐points. Development of the cerebellum requires many concurrent processes including gross morphological changes such as foliation, afferent arrival, and overlapping periods of cell birth, migration, and patterning of Purkinje cells and afferent fibers into longitudinal zones. Abbreviations: CFs, climbing fibers; CN, cerebellar nuclei; CR+, calretinin‐positive; EGL, external granular layer; GCPs; granule cell precursors; GLIs, granular layer interneurons; GluR2+, GluR2‐positive; IGL, internal granular layer; MFs, mossy fibers; MLIs, molecular layer interneurons; NTZ, nuclear transitory zone; PC, Purkinje cell; PN, pontine nuclei; RL, rhombic lip; SC, spinocerebellar; UBCs, unipolar brush cells; VG, vestibular ganglion; VN, vestibular nuclei; VZ, ventricular zone. (b) A series of images that capture the morphological changes that occur during mouse cerebellar development. At E12, the cerebellum has established its bilateral wing‐like architecture. By E16, the midline vermis region has filled in, although it is not anatomically distinguished from the hemispheres. Shortly afterward at E17, lobule formation begins with the establishment of the cardinal lobes. After birth, specific lobules form and cerebellar size increases exponentially. By P28, the molecular patterns and gross anatomical architecture of the cerebellum are considered mature. The cerebella shown in the E12 and E16 panels are outlined with dotted white lines. The cerebellum in the P0 panel is dyed with methylene blue in order to enhance the visibility of the surface foliation pattern at birth. Abbreviations: Mb, Midbrain; Cb, Cerebellum; Bs, Brainstem. All scale bars are 1 mm.

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