RT Journal Article SR Electronic T1 The NDNF-like factor Nord is a Hedgehog-induced extracellular BMP modulator that regulates Drosophila wing patterning and growth JF bioRxiv FD Cold Spring Harbor Laboratory SP 2021.09.06.459106 DO 10.1101/2021.09.06.459106 A1 Yang, Shu A1 Wu, Xuefeng A1 Daoutidou, Euphrosyne I. A1 Zhang, Ya A1 Shimell, MaryJane A1 Chuang, Kun-Han A1 Peterson, Aidan J. A1 O’Connor, Michael B. A1 Zheng, Xiaoyan YR 2021 UL http://biorxiv.org/content/early/2021/09/06/2021.09.06.459106.abstract AB Hedgehog (Hh) and bone morphogenetic proteins (BMPs) pattern the developing Drosophila wing by functioning as short- and long-range morphogens, respectively. Here, we show that a previously unknown Hh-dependent mechanism fine-tunes the activity of BMPs. Through genome-wide expression profiling of the Drosophila wing imaginal discs, we identify nord as a novel target gene of the Hh signaling pathway. Nord is related to the vertebrate Neuron Derived Neurotrophic Factor (NDNF) involved in Congenital Hypogonadotropic Hypogonadism and several types of cancer. Loss- and gain-of-function analyses implicate Nord in the regulation of wing growth and proper crossvein patterning. At the molecular level, we present biochemical evidence that Nord is a secreted BMP-binding protein and localizes to the extracellular matrix. Nord binds to Decapentaplegic (Dpp) or the heterodimer Dpp-Glass bottom boat (Gbb) to modulate their release and activity. Furthermore, we demonstrate that Nord is a dosage-depend biphasic BMP modulator, where low levels of Nord promote and high levels inhibit BMP signaling. Taken together, we propose that Hh-induced Nord expression fine tunes both the range and strength of BMP signaling in the developing Drosophila wing.One sentence summary The NDNF-like factor Nord is a Hedgehog-induced and extracellular-localized biphasic BMP modulator that regulates Drosophila wing patterning and growthCompeting Interest StatementThe authors have declared no competing interest.