Exploring the role of aryl hydrocarbon receptor in the neural development and the tumorigenesis of neuroblastoma.

Project Details

Description

Neuroblastoma (NB) is the most common malignant disease of infancy. MYCN amplification is a prognostic factor of NB. It indicates a highly malignant disease and poor patient prognosis. Our previous study found that the expression level of aryl hydrocarbon receptor (AHR) was reversely correlated with the MYCN expression in NB tumors. Positive AHR expression by immunostaining of NB tumors correlated well with histological grade of differentiation and predicted a favorable prognosis. In addition, ectopic expression of AHR could promote neural differentiation of NB cells. Recently, AHR was found to be expressed in cerebellar granular neuronal precursor (GNPs) in the early postnatal period, where it regulates the growth and differentiation of granule neuroblasts. AHR-deficient mice also display diminished neuronal differentiation in the dentate gyrus, and knockout of AHR causes oculomotor and optic nerve deficits in a mouse model. All these evidence support the idea that AHR plays an important role in regulating neural development and may have an impact on the tumorigenesis of NB. Our previous study has preliminarily proved that AHR signaling mediates both neuronal and myelinating glial cell differentiation by zebrafish models. In this proposed project, we aim to use mouse models to further investigate the endogenous role of AHR in neural development that might provide us important information on the tumorigenesis of NB. Specifically, we propose the project with the following three aims:Aim I. Determining the expression profile of AHR in the developing mouse brain. To understand the role of AHR in the neural development, the expression patterns of AHR and the downstream gene CYP1A1 will be first analyzed. Brain tissues from the mouse embryos in different embryonic stages will be collected and analyzed by the in situ hybridization (ISH), immunohistochemistry (IHC) staining and real-time PCR. Aim II. Determining the role of AHR signaling in neural development by the mNSCs model. The mNSCs will be isolated from the brain of wild-type C57BL/6 mice and be induced to differentiate to neurons, astrocytes or oligodendrocytes for examining the expression changes of AHR during cell fate choice. In addition, the expression level of markers for different cell lineage development will be examined by ICC in AHR transfected or AHR ligands treated mNSC. By in utero electroporation, the effect of AHR in neural development will be investigated in vivo.Aim III. Further confirming the effect of AHR signaling in neural development and the tumorigenesis of NB by mNSCs from AHR KO mice (AKO-mNSCs). To examine whether AHR deficiency causes abnormal neural differentiation, AKO-mNSCs will be treated with differentiation-inducing factors. Then, the stemness and cell differentiation status of AKO-mNSCs will be analyzed comparing with WT-mNSC. Lastly, a possible mechanism that loss-of-AHR signaling and high MYCN expression cooperatively contribute to the tumorigenesis of NB will be examined by the ectopic expression of MYCN in AKO-mNSCs.
StatusFinished
Effective start/end date1/09/2031/07/21

UN Sustainable Development Goals

In 2015, UN member states agreed to 17 global Sustainable Development Goals (SDGs) to end poverty, protect the planet and ensure prosperity for all. This project contributes towards the following SDG(s):

  • SDG 3 - Good Health and Well-being
  • SDG 12 - Responsible Consumption and Production
  • SDG 17 - Partnerships for the Goals

Keywords

  • Neuroblastoma
  • Aryl hydrocarbon receptor
  • neural stem cell
  • neural development

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