IRX2 and NPTX1 differential regulation of β-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. Although 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 used a combination of genetic and pharmacological approaches to demonstrate that MEK-regulated cell growth is mediated by β-catenin through independent mechanisms involving IRX2 control of CTNNB1 transcription and NPTX1 stabilization of β-catenin protein levels. These results provide new mechanistic insights into MEK regulation of human brain cell function.