Fig 7

MYCN overexpression produces a cellular population with aberrant gene expression and a dampened BMP response.

A,C) Normal NCC differentiation towards SAP fate requires a fine-tuned expression of transcription factors and differentiation effectors. sox10 and crestin (in zebrafish) are expressed during early NCC specification and retain their expression during NCC migration. As NCC undergo epithelial to mesenchymal transition (EMT) and migrate they transiently express mycn. When NCC receive SAP differentiation signals, they downregulate expression of early NCC genes and commence the expression of genes required for sympathoadrenal specification like phox2bb, elavl3 and dbh. C) The ectopic expression of MYCN causes a change in the developmental program and timing of these cells, where NCC markers like crestin and sox10, present expanded expression concurrent with SAP differentiation markers like phox2bb, elavl3, and dbh. B,D) Proposed model where MYCN overexpression disrupts SAP neuronal differentiation, possibly via alterations in BMP signaling. B) SAP development progresses correctly when the physiological levels of MYCN are controlled over time, and cells are able to respond to BMP signals and reach their final fate. D) In MYCN-overexpressing conditions, cells can no longer establish a proper BMP response to undergo neuronal differentiation, creating an aberrant population that contains NCC and SAP markers.