Elsevier

Molecular Genetics and Metabolism

Volume 80, Issues 1–2, September–October 2003, Pages 54-65
Molecular Genetics and Metabolism

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Development and malformations of the cerebellum in mice

https://doi.org/10.1016/j.ymgme.2003.08.019Get rights and content

Abstract

The cerebellum is the primary motor coordination center of the CNS and is also involved in cognitive processing and sensory discrimination. Multiple cerebellar malformations have been described in humans, however, their developmental and genetic etiologies currently remain largely unknown. In contrast, there is extensive literature describing cerebellar malformations in the mouse. During the past decade, analysis of both spontaneous and gene-targeted neurological mutant mice has provided significant insight into the molecular and cellular mechanisms that regulate cerebellar development. Cerebellar development occurs in several distinct but interconnected steps. These include the establishment of the cerebellar territory along anterior–posterior and dorsal–ventral axes of the embryo, initial specification of the cerebellar cell types, their subsequent proliferation, differentiation and migration, and, finally, the interconnection of the cerebellar circuitry. Our understanding of the basis of these developmental processes is certain to provide insight into the nature of human cerebellar malformations.

Introduction

The cerebellum has long been recognized as the primary center of motor coordination in the central nervous system (CNS) [1]. Recent studies in humans have also implicated the cerebellum in cognitive processing and sensory discrimination in medical conditions as diverse as pervasive developmental disorders, autism, and cerebellar vascular injuries [2], [3], [4], [5], [6]. Numerous cerebellar and related hindbrain malformations have been described in humans including cerebellar vermian hypoplasia, pontocerebellar hypoplasia, Dandy–Walker malformation and molar tooth malformations. Most are associated with significant risk for mental retardation and other developmental disabilities such as ataxia, cerebral palsy and epilepsy. Although commonly described in the clinical literature, only very recently has there been significant effort directed towards classifying and precisely defining human congenital cerebellar malformations [7], [8], [9]. The developmental and genetic etiologies of these human cerebellar malformations remain largely unknown. This is in contrast to the rich literature describing the molecular mechanisms of cerebellar malformations in the mouse. Given the high degree of conservation of cerebellar anatomy and function between both the mouse and human, an understanding of mouse cerebellar development is likely to shed new insight upon the developmental basis of human cerebellar malformations.

The cerebellum is a relatively simple CNS structure with well-defined anatomy and physiology (Fig. 1). The cerebellum is morphologically divided into a central vermis, which is flanked by lateral hemispheres. Both the vermis and hemispheres are subdivided by a series of parallel fissures defining a conserved pattern of folia. The function of the cerebellum depends on the actions of three principal neuronal subclasses; (1) granule cells, (2) Purkinje cells, and (3) deep cerebellar neurons. Each neuronal type has a stereotypic and distinct morphology and is located in a discrete lamina within the cerebellum. In the adult cerebellum precise connections between the principal neurons are arranged in a stereotyped circuitry that is repeated throughout the cerebellum (Fig. 1C). Information is sent to the cerebellum via the precerebellar system, a group of nuclei including the pontine nuclei, and spinocerebellar pathways that send projections (mossy fibers) to granule neurons. Information to Purkinje cells from axons of granule cells (parallel fibers) is modulated by input from the climbing fibers of the inferior olivary complex, which also synapse with the dendrites of Purkinje cells. Purkinje cells, in turn, send axons to deep cerebellar nuclei, which provide the primary output from the cerebellar cortex [10], [11].

Development of the cerebellum involves integration of both intrinsic and cell extrinsic events controlled by multiple genetic cascades. Cerebellar development occurs in several distinct but interconnected stages. They include establishing of the cerebellar territory along anterior–posterior (AP) and dorsal–ventral (DV) axes of the neural tube, initial specification of the cerebellar cell types, their subsequent proliferation, differentiation and migration, and finally, formation of the cerebellar circuitry. Much of our current understanding of cellular and molecular mechanisms directing formation of the cerebellum has come from analysis of mutant mice with cerebellar malformations. Approximately 60 spontaneous mouse mutant strains with cerebellar malformations have been identified over the last 100 years (http://www.informatics.jax.org/). Disruptions in cerebellar development and/or function often result in a typical uncoordinated phenotype in mice. Names of these mutant strains such as weaver, lurcher, reeler, and swaying clearly reflect this obvious uncoordinated phenotype. With the introduction of gene targeting technologies in the late 1980s, the roles of numerous additional genes in cerebellar development have been described enhancing our knowledge of the cerebellar development. Here we first briefly outline normal cerebellar development, and then review what is known about the molecular mechanisms that control development of the cerebellum in mouse and how these findings can help us to understand the nature of human cerebellar disorders.

Section snippets

Overview of cerebellar development

The vertebrate CNS derives from the neural plate, an epithelial sheet that arises from the dorsal ectoderm of the gastrula-stage embryo. Subsequently, the neural plate closes to form the neural tube, which becomes patterned along its AP and DV axes. Shortly after neural tube closure, a series of vesicles can be clearly distinguished morphologically at the anterior end of the neural tube of the mouse embryo, indicating its patterning along AP axis (Fig. 2). The most anterior end of the neural

Otx2 and Gbx2 determine the position of IsO

Gene targeting experiments have revealed that two genes: Otx2 and Gbx2, mouse homologues of the Drosophila genes orthodenticle and unplugged, respectively, play primary roles in the positioning of the IsO, and thus, in determining of the anterior limit of the cerebellar territory [29], [30], [31]. In the mouse neural plate and neural tube, these genes are expressed in complementary patterns. Otx2 is expressed in the anterior CNS, with a posterior limit of expression at the mid/hindbrain

Establishment of the cerebellar territory along DV axis

Although transplantation studies have clearly demonstrated that the cerebellum arises from the dorsolateral domain of rhombomere 1 [14], [20], little is known about the mechanisms involved in dorsoventral patterning of this region. This is in stark contrast to our understanding of the DV patterning mechanisms at the level of the spinal cord. In the developing spinal cord this process involves the action of two opposing signaling pathways. Peptides of the transforming growth factor-β (Tgfβ) and

Initial specification of the cerebellar cell types

It is believed that the establishment of the identities of each cerebellar cell type depends on the activity of different sets of genes regulated by local signaling molecules. The first gene that has been identified in this regard is Math1, the mouse homologue of the Drosophila proneural gene atonal. Math1 is expressed in germinal epithelium of the rhombic lip and many of its derivatives. A targeted mutation of Math1 leads to a complete loss of several rhombic lip derivatives in adult mice

Regulation of neuronal number in the cerebellum

The cerebellum is a highly ordered structure composed of defined numbers of different cellular types. Numerous studies have demonstrated that during cerebellar development, the generation of the proper number of cells is achieved by tight regulation of programs that control proliferation, cell cycle withdrawal and differentiation, and apoptosis of cells of each cellular type. Recently, significant progress has been achieved in the understanding of the genetic regulation of these programs mostly

Neuronal migration during cerebellar development

A number of molecular pathways have been implicated in migration of both Purkinje cells and granule neurons [84]. Analysis of the spontaneous neurological mouse mutant rostral cerebellar malformation (rcm) shed light on molecular mechanisms controlling early migration events in the embryonic cerebellum [85]. rcm/rcm animals have a hypoplastic cerebellar cortex and a reduction in the number of folia in the midline sagittal regions. This phenotype results from over-migration of granule cell

Establishing cerebellar connectivity

The precise formation of the neuronal circuitry is the final step of cerebellar development and is necessary for the cerebellum to function as a coordination center. It has been well documented that establishing connectivity is closely associated with the terminal differentiation of cerebellar neurons [26], however, relatively little is known about the cellular and molecular mechanism that control this process.

Although the cerebellar circuitry described in Fig. 1C is reiterated across the

Cerebellar development in mice and human cerebellar malformations

The delineation of the molecular and cellular mechanisms by which the cerebellum is formed is of interest from both a basic research and a clinical standpoint. Genetic and experimental manipulations in the mouse have greatly enhanced our knowledge regarding the mechanisms and molecules that drive cerebellar development. In contrast, our current understanding of the developmental basis of human cerebellar malformations is much less sophisticated, and their molecular basis remains largely

Conclusion

Largely as a result of mouse mutant analysis, extensive progress has been made in understanding the cellular and molecular mechanisms directing cerebellar development. It is clear however, that much remains to be elucidated. Currently, numerous additional mouse mutants are being generated as a result of ongoing mouse mutagenesis programs worldwide. Molecular and phenotypic analysis of these and the many classical neurological mutants will continue to reveal important details of complex process

Acknowledgements

We are grateful to Anne Lindgren, Inessa Grinberg, Ekaterina Steshina, and Melissa Parisi for helpful discussion of the manuscript. We also thank Phyllis Faust for the photograph included as Fig. 1B.

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