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The cerebellum represents 10% of the brain's total volume, but contains more than half of our neurons. It acts as a coordination centre, using sensory inputs from the periphery to fine-tune

our movement and balance. It is one of the first structures in the brain to begin to differentiate, but one of the last to mature, and its cellular organization continues to change for many

months after birth. The study of mouse homologues of Drosophila genes has provided valuable insights into the molecular basis of cerebellar development.

In humans, the cerebellum develops from the dorsal region of the posterior neural tube, and its cells arise from two germinal matrices. Most cells are derived from the ventricular zone, but

the granule neurons come from a specialized germinal matrix called the rhombic lip.

The mesencephalon and metencephalon both contribute to the developing mouse cerebellum. The patterning of these two regions depends on signals from the isthmus organizer (IO), located just

caudal to their junction. Otx2 and Gbx2 are central to IO development. Otx2 is expressed in the mesencephalon, with a posterior boundary at the rostral metencephalon; Gbx2 is expressed in

the metencephalon, and its anterior boundary abuts the Otx2 boundary. Reciprocal repression maintains a sharp boundary between these domains. Otx2 and Gbx2 form part of a regulatory loop

that includes Wnt1, En1 and Fgf8. Many other genes, including members of the Pax and Hox families, are also involved in patterning this region.

Purkinje cells (PCs), Golgi neurons, stellate and basket cells all arise from the ventricular neuroepithelium. PCs are born around embryonic day 13, and they migrate along radial glial

fibres into the cerebellar anlage. During their final maturation phase, PCs develop extensive dendritic arbors and synapse onto granule neurons. This depends on granule neuron signals,

probably including Wnt3. Various growth factors are required for PC survival, including nerve growth factor, acetylcholine, neurotrophin 4/5, brain-derived neurotrophic factor and ciliary

neurotrophic factor.

The rhombic lip, located between the fourth ventricle and the metencephalic roof plate, gives rise to granule neurons. Proliferation in its germinal epithelium is governed by the Math1 gene.

Rhombic lip cells migrate to the cerebellar anlage and settle on its periphery to form the external granule layer, another zone of proliferation. As the cells begin to migrate, they express

markers that include RU49/Zipro1, Zic1 and Zic3. RU49/Zipro1 and Zic1 are thought to be involved in cell proliferation, which requires interaction with PCs. PCs might release a diffusible

factor such as sonic hedgehog (Shh), and Zic1 could control cell proliferation by indirectly regulating the Shh pathway. The final stage of granule neuron maturation occurs after precursor

cell migration into the inner granule layer.

Many genes, including En1, En2, Pax2, Wnt7b, and some of the ephrins and their receptors, show characteristic patterns of spatial expression in the cerebellum, but only En2 has been studied

specifically for its role in compartmentalization. In addition to the patterning genes, several other gene families, such as the heat shock proteins and proteins involved in neuronal

migration, are also expressed in specific patterns. Spatial- and temporal-specific knockout strategies should yield more information about the roles of these genes in patterning the

cerebellum.

The cerebellum is one of the first brain structures to begin to differentiate, yet it is one of the last to achieve maturity — the cellular organization of the cerebellum continues to change

for many months after birth. This protracted developmental process creates a special susceptibility to disruptions during embryogenesis and makes the cerebellum highly amenable to study.

Over the past few years, genetic research has provided a great deal of information about the molecular events directing the formation of the cerebellum. Knowledge of these mechanisms should

enable us to address the nature of human diseases that have their root in developmental processes.

The authors would like to thank V. Brandt for her input; H.Y.Z. is a Howard Hughes Medical Institute Investigator; V.Y.W. is supported by a pre-doctoral NRSA fellowship and is a McNair

Scholar.

Programme in Developmental Biology, Baylor College of Medicine, 1 Baylor Plaza, Houston, 77030, Texas, USA

Departments of Pediatrics, Division of Neuroscience, Neurology, Molecular and Human Genetics, and Howard Hughes Medical Institute, Baylor College of Medicine, 1 Baylor Plaza, Houston, 77030,

Texas, USA

Cerebellar interneurons located in the granule cell layer. Their axonal terminals form part of the cerebellar glomeruli.

Cerebellar interneurons located in the molecular layer that project to Purkinje cells.

Interneurons that send their axons to the cell body of the postsynaptic cell, surrounding it with a structure akin to a basket.

Downward displacement of the cerebellum and brainstem; the spinal cord might also be deformed.

The axons of cerebellar granule cells. Parallel fibres emerge from the molecular layer of the cerebellar cortex towards the periphery, where they extend branches perpendicular to the main

axis of the Purkinje neurons and form the so-called en passant synapses with this cell type.

Cerebellar afferents that arise from the inferior olivary nucleus, each of which forms multiple synapses with a single Purkinje cell.

A chick that has received a piece of quail tissue as a transplant; the derivative of the transplanted tissue allows fate-mapping analysis.

A narrow section of the brainstem, which separates the midbrain from the pons.

The point of fusion of the neural folds, forming the dorsal-most part of the neural tube.

A syndrome in which the position of the internal organs is reversed.

Causes basal cell carcinoma and, in 10% of cases, medulloblastoma.

A mutant molecule capable of forming a heteromeric complex with the normal molecule, knocking out the activity of the entire complex.

Cerebellar afferents that constitute the main input to the granule cells. They also project to the deep cerebellar nuclei.

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