The role of the ubiquitin proteasome system in cerebellar development and medulloblastoma

TL;DR

This paper explores how the ubiquitin proteasome system influences cerebellar development and the formation of medulloblastoma, a type of childhood brain tumor.

Contribution

The paper proposes a novel hypothesis that proteasome dysfunction may drive medulloblastoma by disrupting granule cell differentiation.

Findings

Proteasome dysfunction during development may lead to abnormal granule cell differentiation and medulloblastoma.

Ubiquitin ligases like β-TrCP, FBW7, Huwe1, and SKP2 play roles in medulloblastoma initiation and progression.

Dysfunction in proteasome activity could explain mutations in DNA repair mechanisms seen in medulloblastoma.

Abstract

Cerebellar granule cells precursors are derived from the upper rhombic lip and migrate tangentially independent of glia along the subpial stream pathway to form the external germinal zone. Postnatally, granule cells migrate from the external germinal zone radially through the Purkinje cell layer, guided by Bergmann glia fibers, to the internal granular cell layer.

Medulloblastomas (MBs) are the most common malignant childhood brain tumor. Many of these tumors develop from precursor cells of the embryonic rhombic lips. Four main groups of MB are recognized. The WNT group of MBs arise primarily from the lower rhombic lip and embryonic brainstem. The SHH group of MBs originate from cerebellar granule cell precursors in the external germinal zone of the embryonic cerebellum. The cellular origins of type 3 and type 4 MBs are not clear.

Several ubiquitin ligases are revealed to be significant factors in development of the cerebellum as well as in the initiation and maintenance of MBs. Proteasome dysfunction at a critical stage of development may be a major factor in determining whether progenitor cells which are destined to become granule cells differentiate normally or become MB cells. We propose the hypothesis that proteasomal activity is essential to regulate the critical transition between proliferating granule cells and differentiated granule cells and that proteasome dysfunction may lead to MB. Proteasome dysfunction could also account for various mutations in MBs resulting from deficiencies in DNA checkpoint and repair mechanisms prior to development of MBs.

Data showing a role for the ubiquitin ligases β-TrCP, FBW7, Huwe1, and SKP2 in MBs suggest the possibility of a classification of MBs based on the expression (over expression or under expression) of specific ubiquitin ligases which function as oncogenes, tumor suppressors or cell cycle regulators.

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