Expression of the ErbB-Neuregulin Signaling Network during Human Cerebellar Development: Implications for the Biology of Mceluilohiastonia1

The four receptor tyrosine kinase I receptors, ErbB-1, ErbB-2, ErbB-3, and KrbB-4, which have been implicated in the development of a variety of normal and malignant tissues, are activated through ligand mediated homoand hctcrodimerization. We have previously reported the frequent coexpression, heterodimerzation, and prognostic significance of ErbB-2 and ErbB-4 in childhood medulloblastoma, an embryonal tumor of the ccrebcllar external granule cell layer (EGL). In the present study, we have used immunohistochemistry and Western blotting analysis to analyze the expression of the 1 i hi! receptors and neuregulin (NRG) 1-a and NRGl-ß ligands during normal human cerebellar development. We demonstrate that ErbB-1, ErbB-3, ErbB-4, and NRG 1-0 display specific temporal and topographical distribution in the cerebellum during intrauterine and postnatal life, and that normal ErbB-NRG signaling in the EGL multi plying zone is likely to be mediated by ErbB-4 and NRGl-ß. In contrast, ErbB-2, which is expressed in 86% of medulloblastomas, could not be detected at any stage of cerebellar development. Therefore, we propose that positive deregulation of ErbB-2 expression in the cerebellar EGL, leading to the formation of a NRGl-ß-driven ErbB-2/ErbB-4 autocrine loop, is an important factor in medulloblastoma tumorigenesis. In further support of this hypothesis, we provide evidence using reverse transcription-PCR analysis that expression of the ErbB-2 and ErbB-4 receptors, but not ErbB-1 or ErbB-3, is deregulated in medulloblastoma compared with normal developing cerebellum. We also demonstrate NRG1-P expression in 87% (n = 46 of 48) of medulloblastoma primary tumors, with the greatest expression levels occurring in tumors with high ErbB-2 and ErbB-4 receptor coexpression. Furthermore, the expression uf all three components of the proposed autocrine loop (i.e., ErbB-2, ErbB-4, and NRGl-ß) was significantly related to the presence of métas tases at diagnosis (P < 0.05).