Journal Article

Bone morphogenetic protein heterodimers assemble heteromeric type I receptor complexes to pattern the dorsoventral axis

Little, Shawn C., Mullins, Mary C.

2009

Overview

Bone morphogenetic proteins (BMPs) regulate zebrafish dorsoventral patterning through two distinct receptor complexes. Surprisingly, BMPs function as an obligate heterodimer of BMP-2 and -7, while BMP homodimers are inactive. Patterning the embryonic dorsoventral axis of both vertebrates and invertebrates requires signalling through bone morphogenetic proteins (BMPs) 1 . Although a well-studied process, the identity of the physiologically relevant BMP signalling complex in the Drosophila melanogaster embryo is controversial 2 , 3 , is generally inferred from cell culture studies and has not been investigated in vertebrates. Here, we demonstrate that dorsoventral patterning in zebrafish, Danio rerio , requires two classes of non-redundant type I BMP receptors, Alk3/6 and Alk8 (activin-like kinases 3/6 and 8). We show, under physiological conditions in the embryo, that these two type I receptor classes form a complex in a manner that depends on Bmp2 and Bmp7. We found that both Bmp2–7 heterodimers, as well as Bmp2 and Bmp7 homodimers, form in the embryo. However, only recombinant ligand heterodimers can activate BMP signalling in the early embryo, whereas a combination of Bmp2 and Bmp7 homodimers cannot. We propose that only heterodimers, signalling through two distinct classes of type I receptor, possess sufficient receptor affinity in an environment of extracellular antagonists to elicit the signalling response required for dorsoventral patterning.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: Activin Receptors - metabolism / Activin Receptors, Type I - genetics / Activin Receptors, Type I - metabolism / Animals / Biomedical and Life Sciences / Body Patterning - physiology / Bone Morphogenetic Protein 2 - genetics / Bone Morphogenetic Protein 2 - metabolism / Bone Morphogenetic Protein 7 - genetics / Bone Morphogenetic Protein 7 - metabolism / Bone Morphogenetic Protein Receptors, Type I - genetics / Bone Morphogenetic Protein Receptors, Type I - metabolism / Bone morphogenetic proteins / Bone Morphogenetic Proteins - genetics / Bone Morphogenetic Proteins - metabolism / Cancer Research / Cell Biology / Cell Nucleus - metabolism / Cell receptors / Cellular signal transduction / Developmental Biology / Embryo, Nonmammalian - abnormalities / Embryo, Nonmammalian - metabolism / Embryos / Genes / Genetic aspects / Insects / Invertebrates / Kinases / letter / Life Sciences / Ligands / Models, Biological / Oligonucleotides, Antisense - genetics / Phosphorylation / Physiological aspects / Physiology / Protein Binding - physiology / RNA, Messenger - antagonists & inhibitors / RNA, Messenger - genetics / Signal Transduction - physiology / Smad1 Protein - metabolism / Smad5 Protein - metabolism / Stem Cells / Vertebrates / Zebrafish - embryology / Zebrafish Proteins - genetics / Zebrafish Proteins - metabolism