The NDNF-like factor Nord is a Hedgehog-induced extracellular BMP modulator that regulates wing patterning and growth

Shu Yang, Department of Anatomy and Cell Biology and the GW Cancer Center, George Washington University School of Medicine and Health Sciences, Washington, United States.
Xuefeng Wu, Department of Anatomy and Cell Biology and the GW Cancer Center, George Washington University School of Medicine and Health Sciences, Washington, United States.
Euphrosyne I. Daoutidou, Department of Genetics, Cell Biology & Development and the Developmental Biology Center, University of Minnesota, Minneapolis, United States.
Ya Zhang, Department of Anatomy and Cell Biology and the GW Cancer Center, George Washington University School of Medicine and Health Sciences, Washington, United States.
MaryJane Shimell, Department of Genetics, Cell Biology & Development and the Developmental Biology Center, University of Minnesota, Minneapolis, United States.
Kun-Han Chuang, Department of Anatomy and Cell Biology and the GW Cancer Center, George Washington University School of Medicine and Health Sciences, Washington, United States.
Aidan J. Peterson, Department of Genetics, Cell Biology & Development and the Developmental Biology Center, University of Minnesota, Minneapolis, United States.
Michael B. O'Connor, Department of Genetics, Cell Biology & Development and the Developmental Biology Center, University of Minnesota, Minneapolis, United States.
Xiaoyan Zheng, Department of Anatomy and Cell Biology and the GW Cancer Center, George Washington University School of Medicine and Health Sciences, Washington, United States.

Document Type

Journal Article

Publication Date

1-17-2022

Journal

eLife

Volume

11

DOI

10.7554/eLife.73357

Keywords

BMP; D. melanogaster; Hedgehog; biphasic modulator; cell biology; developmental biology; growth; patterning; signal transduction

Abstract

Hedgehog (Hh) and Bone Morphogenetic Proteins (BMPs) pattern the developing 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 wing imaginal discs, we identify 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-dependent 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 wing.

Department

Anatomy and Regenerative Biology

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