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

Department of Cell and Developmental Biology, University of Pennsylvania School of Medicine, 1211 BRBII/III, 421 Curie Boulevard., Philadelphia, PA 19104-6058, USA.
Nature Cell Biology (Impact Factor: 20.06). 05/2009; 11(5):637-43. DOI: 10.1038/ncb1870
Source: PubMed

ABSTRACT Patterning the embryonic dorsoventral axis of both vertebrates and invertebrates requires signalling through bone morphogenetic proteins (BMPs). Although a well-studied process, the identity of the physiologically relevant BMP signalling complex in the Drosophila melanogaster embryo is controversial, 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.

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Available from: Shawn C Little, Aug 13, 2015
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    • "To delineate the contribution of each BMP type I receptor in the formation of lymphatic vessel, we attenuated the level of Alk1, Alk2, Alk3, and Alk3b activities in zebrafish. Consistent with a previous report (Little and Mullins, 2009), the injections of "
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    • "(For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.) other proteins as for example BMP-2/BMP-7 [23]. Furthermore the entire proteins can undergo post-translational modifications such as phosphorylations, acetylations or palmitoylations that can have an effect on their functionality [24] [25]. "
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    • "Six of these cysteines form disulphide bonds and the seventh (which is not present in GDF3, GDF9 or BMP15) forms a disulphide bond with another monomer, to form the biologically-active dimeric molecule. The BMPs generally act as homodimers, although heteromeric complexes of BMP2/6, BMP2/7 and BMP2b/7 have been described (Little & Mullins, 2009; Sieber et al., 2009). Many of the BMPs have been found to create complexes with their respective prodomains following release into the extracellular environment as active dimers (for review, see Bragdon et al., 2011). "
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