Neuroblastoma Phox2b Variants Stimulate Proliferation and Dedifferentiation of Immature Sympathetic Neurons

• Published in: The Journal of neuroscience Vol. 30; no. 3; pp. 905 - 915
• Main Authors: Reiff, Tobias, Tsarovina, Konstantina, Majdazari, Afsaneh, Schmidt, Mirko, del Pino, Isabel, Rohrer, Hermann
• Format: Journal Article
• Language: English
• Published: United States Soc Neuroscience 20.01.2010; Society for Neuroscience
• Subjects: Animals; Basic Helix-Loop-Helix Transcription Factors - genetics; Basic Helix-Loop-Helix Transcription Factors - metabolism; Brain-Derived Neurotrophic Factor - pharmacology; Bromodeoxyuridine - metabolism; Cell Count - methods; Cell Differentiation - drug effects; Cell Differentiation - physiology; Cell Line, Tumor; Cell Proliferation - drug effects; Cells, Cultured; Chick Embryo; Embryo, Mammalian; Ganglia, Sympathetic - cytology; Gene Expression Regulation, Developmental - drug effects; Gene Expression Regulation, Developmental - genetics; Gene Expression Regulation, Neoplastic - genetics; Green Fluorescent Proteins - genetics; Histones - metabolism; Homeodomain Proteins - chemistry; Homeodomain Proteins - genetics; Homeodomain Proteins - physiology; Immunoprecipitation; Inhibitor of Differentiation Protein 2 - genetics; Inhibitor of Differentiation Protein 2 - metabolism; Mice; Mice, Inbred C57BL; Mutation - physiology; Neuroblastoma; Neurons; RNA, Small Interfering - pharmacology; Transcription Factors - chemistry; Transcription Factors - genetics; Transcription Factors - metabolism; Transcription Factors - physiology; Tyrosine 3-Monooxygenase - metabolism
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/JNEUROSCI.5368-09.2010

Neuroblastoma is a pediatric tumor that is thought to arise from autonomic precursors in the neural crest. Mutations in the PHOX2B gene have been observed in familial and sporadic forms of neuroblastoma and represent the first defined genetic predisposition for neuroblastoma. Here, we address the mechanisms that may underlie this predisposition, comparing the function of wild-type and mutant Phox2b proteins ectopically expressed in proliferating, embryonic sympathetic neurons. Phox2b displays a strong antiproliferative effect, which is lost in all Phox2b neuroblastoma variants analyzed. In contrast, an increase in sympathetic neuron proliferation is elicited by Phox2b variants with mutations in the homeodomain when endogenous Phox2b levels are lowered by siRNA-mediated knockdown to mimic the situation of heterozygous PHOX2B mutations in neuroblastoma. The increased proliferation is blocked by Hand2 knockdown and the antiproliferative Phox2b effects are rescued by Hand2 overexpression, implying Hand2 in Phox2b-mediated proliferation control. A Phox2b variant with a nonsense mutation in the homeodomain elicits, in addition, a decreased expression of characteristic marker genes. Together, these results suggest that PHOX2B mutations predispose to neuroblastoma by increasing proliferation and promoting dedifferentiation of cells in the sympathoadrenergic lineage.