IRX2 and NPTX1 differential regulation of b-catenin underlies MEK-mediated proliferation in human neuroglial cells

The two major genomic alterations in pediatric pilocytic astrocytoma (PA) are NF1 loss and KIAA1549: BRAF rearrangement. While these molecular changes result in increased MEK activity and tumor growth, it is not clear exactly how MEK controls human neuroglial cell proliferation. Leveraging human induced pluripotent stem cells harboring these PA-associated alterations, we use a combination of genetic and pharmacological approaches to demonstrate that MEK-regulated cell growth is mediated by b-catenin through independent mechanisms involving IRX2 control of CTNNB transcription and NPTX1 stabilization of b-catenin protein levels. These results provide new mechanistic insights into MEK regulation of human brain cell function