Human KIAA0922/TMEM131L encodes a transmembrane protein, TMEM131L, that regulates the canonical Wnt/beta-catenin signaling pathway by eliciting the lysosome-dependent degradation of phosphorylated LRP6 co-receptor. Here, we use a heterospecific Drosophila transgenic model to examine the potential evolutionary conservation of TMEM131L function. Analysis of TMEM131L transgenic flies shows that TMEM131L interference with the Wnt pathway results primarily from a Notch-dependent decrease in Wingless production. Consistently, lentivirus-mediated overexpression of TMEM131L in human CD34(+) hematopoietic progenitor cells leads to decreased susceptibility to Notchl ligation and defective commitment toward the T lineage. These results show that TMEM131L corresponds to an evolutionary conserved regulator of the Notch signaling pathway. (C) 2017 Elsevier Inc. All rights reserved.