Abstract
Heterozygous germline mutations and deletions in PHOX2B, a key regulator of autonomic neuron development, predispose to neuroblastoma, a tumor of the peripheral sympathetic nervous system. To gain insight into the oncogenic mechanisms engaged by these changes, we used zebrafish models to study the functional consequences of aberrant PHOX2B expression in the cells of the developing sympathetic nervous system. Allelic deficiency, modeled by phox2b morpholino knockdown, led to a decrease in the terminal differentiation markers th and dbh in sympathetic ganglion cells. The same effect was seen on overexpression of two distinct neuroblastoma-associated frameshift mutations, 676delG and K155X - but not the R100L missense mutation - in the presence of endogenous Phox2b, pointing to their dominant-negative effects. We demonstrate that Phox2b is capable of regulating itself as well as ascl1, and that phox2b deficiency uncouples this autoregulatory mechanism, leading to inhibition of sympathetic neuron differentiation. This effect on terminal differentiation is associated with an increased number of phox2b+, ascl1+, elavl3− cells that respond poorly to retinoic acid. These findings suggest that a reduced dosage of PHOX2B during development, through either a heterozygous deletion or dominant-negative mutation, imposes a block in the differentiation of sympathetic neuronal precursors, resulting in a cell population that is likely to be susceptible to secondary transforming events.
Highlights
Neuroblastoma is an embryonal malignancy of the peripheral sympathetic nervous system (PSNS) that arises from the developing neural crest and manifests as neoplasms in sympathetic ganglia or adrenal medulla
We demonstrate that phox2b gene ‘‘dosage’’ is important for normal differentiation of sympathetic neurons in the zebrafish and suggest that the population of immature cells resulting from a decreased dosage of this pivotal factor may be susceptible to secondary mutations that could lead to neuroblastoma
We demonstrate further that the decrease in terminal differentiation was associated with an increased number of undifferentiated sympathetic neuronal precursors that were resistant to the effects of retinoic acid (RA), and generated a pool of developmentally arrested cells that could serve as targets for future transforming events
Summary
Neuroblastoma is an embryonal malignancy of the peripheral sympathetic nervous system (PSNS) that arises from the developing neural crest and manifests as neoplasms in sympathetic ganglia or adrenal medulla. A defining feature of neuroblastic tumors is their broad spectrum of cellular differentiation, ranging from undifferentiated cells that indicate a poor prognosis to those showing greater differentiation and predicting a generally favorable outcome [2] This heterogeneity suggests that dysregulated differentiation of sympathetic progenitor cells plays a key role in neuroblastoma pathogenesis. Direct evidence for this model comes from the identification of heterozygous germline mutations in the homeodomain transcription factor PHOX2B, a regulator of sympathetic neuronal differentiation [3,4,5,6,7,8].
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