Chapter 8 - Cerebellum: Development and Medulloblastoma

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Abstract

In the last 20 years, it has become clear that developmental genes and their regulators, noncoding RNAs including microRNAs and long-noncoding RNAs, within signaling pathways play a critical role in the pathogenesis of cancer. Many of these pathways were first identified in genetic screens in Drosophila and other lower organisms. Mammalian orthologs were subsequently identified and genes within the pathways cloned and found to regulate cell growth. Genes and pathways expressed during embryonic development, including the Notch, Wnt/β-Catenin, TGF-β/BMP, Shh/Patched, and Hippo pathways are mutated, lost, or aberrantly regulated in a wide variety of human cancers, including skin, breast, blood, and brain cancers, including medulloblastoma. These biochemical pathways affect cell fate determination, axis formation, and patterning during development and regulate tissue homeostasis and regeneration in adults.

Medulloblastoma, the most common malignant nervous system tumor in childhood, are thought to arise from disruptions in cerebellar development [reviewed by Marino, S. (2005)]. Defining the extracellular cues and intracellular signaling pathways that control cerebellar neurogenesis, especially granule cell progenitor (GCP) proliferation and differentiation has been useful for developing models to unravel the mechanisms underlying medulloblastoma formation and growth. In this chapter, we will review the development of the cerebellar cortex, highlighting signaling pathways of potential relevance to tumorigenesis.

Introduction

In their classical treatise on brain tumors, Bailey and Cushing wrote, “the histogenesis of the brain furnishes the indispensable background for an understanding of its tumors” (Bailey and Cushing, 1926). The idea that tumors form from specific populations of immature neurons suggests that common mechanisms underlie development and tumor formation. In the developing cerebellum, precursors of the granule cell are thought to give rise to medulloblastomas, (Bailey and Cushing, 1925) the most common childhood primary CNS tumor (Packer et al., 1999). Medulloblastomas arise in the cerebellar vermis and spread rapidly through the cerebrospinal pathways, where they form tumors of variable size along the ventricles (Packer et al., 1999). Medulloblastomas are a diverse set of tumors as evidenced by several criteria including differing histopathologies (Louis et al., 2007). The most aggressive forms of the disease occur in infants and young children. Although current therapy cure a large proportion of patients, long-term survivors are at significant risk of cognitive and psychological deficits (Levisohn et al., 2000) due to the effects of current treatment protocols that include resection, irradiation, and chemotherapy.

Section snippets

Cerebellar Development

The cerebellar cortex is a remarkably simple laminar structure, with two principal neurons, the granule cell and the Purkinje cell, and a diverse set of interneurons, which modulate the output of the Purkinje cell to the cerebellar nuclei (Palay and Chan-Palay, 1974). The most prevalent neuronal subclass within the cerebellum, indeed within the entire mammalian central nervous system, is the cerebellar granule neuron. Granule neurons serve an essential role in coordinating afferent input to and

Medulloblastoma

Medulloblastoma is the most common malignant pediatric brain tumor with about 1000 new cases every year worldwide and a mean age between 3 and 7 years (Fogarty et al., 2005). Medulloblastoma, a cancer of the cerebellum, (Fig. 8.10), is a heterogenous class of embryonal tumors, that include subgroups with genetic anomalies in developmental pathways that are critical for normal cerebellar development. In the last 10 years a variety of studies, including analyses of primary human patient

Acknowledgments

We thank Joshua Stokes from Biomedical Communication for the drawing of the figures; Dr. Eve-Ellen Govek for reading the chapter; and Drs. David Ellison, Richard Gilbertson, Frederique Zindy, Jane Johnson, and Carol A. Mason for providing illustrations used in this chapter. This work was funded by NIH grants CA-096832 (M.F.R), NINDS R01 NS051778-05 (M. E. H), the Children's Brain Tumor Foundation (M.F.R), the Pediatric Brain Tumor Foundation (M. F. R), the American Brain Tumor Foundation

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