The BMP-Binding Protein Crossveinless 2 Is a Short-Range, Concentration-Dependent, Biphasic Modulator of BMP Signaling in Drosophila

Serpe, Mihaela; Umulis, David M.; Ralston, Amy; Chen, Jun; Olson, David J.; Avanesov, Andrei; Othmer, Hans G.; O’Connor, Michael B.; Blair, Seth S.

doi:10.1016/j.devcel.2008.03.023

Cited by 155 publications

(272 citation statements)

References 39 publications

Supporting

Mentioning

255

Contrasting

Order By: Relevance

“…Mutation of dally impairs DPP signaling in most parts of the wing disc but increases it near the source of DPP. Similar biphasic activity has been observed in Crossveinless 2 and DLP, which are proposed to act as "exchange factors" (25,32,33). Collectively, these observations indicated that our in vitro systems devised in this study recapitulate well the molecular events involved in BMP-HSPG signaling in living animals.…”

Section: Discussionsupporting

confidence: 58%

Novel Contact-dependent Bone Morphogenetic Protein (BMP) Signaling Mediated by Heparan Sulfate Proteoglycans

Dejima

Kanai

Akiyama

et al. 2011

Journal of Biological Chemistry

View full text Add to dashboard Cite

We previously proposed a model that DALLY, a Drosophila glypican, acts as a trans co-receptor to regulate BMP signaling in the germ line stem cell niche. To investigate the molecular mechanisms of contact-dependent BMP signaling, we developed novel in vitro assay systems to monitor trans signaling using Drosophila S2 cells. Using immunoblot-based as well as single-cell assay systems, we present evidence that Drosophila glypicans indeed enhance BMP signaling in trans in a contactdependent manner in vitro. Our analysis showed that heparan sulfate modification is required for the trans co-receptor activity of DALLY. Two BMP-like molecules, Decapentaplegic (DPP) and Glass bottom boat, can mediate trans signaling through a heparan sulfate proteoglycan co-receptor in S2 cells. The in vitro systems reflect the molecular characteristics of heparan sulfate proteoglycan functions observed previously in vivo, such as ligand specificity and biphasic activity dependent on the ligand dosage. In addition, experiments using a DALLY-coated surface suggested that DALLY regulates DPP signaling in trans by its effect on the stability of DPP protein on the surface of the contacting cells. Our findings provide the molecular foundation for novel contact-dependent signaling, which defines the physical space of the stem cell niche in vivo. Bone morphogenetic proteins (BMPs)2 play critical roles in cell-cell communication during animal development. Remarkably, these molecules mediate both long and short range signaling dependent on context. For example, Decapentaplegic (DPP), a Drosophila homologue of BMPs, acts as a long range morphogen in the developing wing and as a contact-dependent niche factor in the female germ line stem cell (GSC) niche. The molecular basis underlying this differential activity of BMPs is not fully understood.Signaling and distribution of BMPs in a tissue are modulated by a class of carbohydrate-modified molecules, heparan sulfate proteoglycans (HSPGs) (1-3). In addition to BMPs, HSPGs serve as co-receptors for a number of other growth factors and morphogens, including FGF, WNT, and Hedgehog (4). HSPGs generally are thought to regulate growth factor signaling on the surface of the signal-receiving cells (5). It has been reported, however, that HSPGs can regulate signaling in trans from neighboring cells in some cases (6, 7).Recent studies demonstrated that HSPGs are essential regulators of the GSC niche in the Drosophila ovary (8, 9). Although it has been well established that DPP regulates the asymmetric division of a GSC (10), the mechanism by which this secreted molecule differentially regulates two daughter cells has been a mystery. We have found previously that DALLY, a Drosophila HSPG of the glypican type, is expressed specifically in the somatic niche cells (the cap cells) contacting GSCs and is required for GSC maintenance (8). Ectopic dally expression in somatic cells in a wide region of the germarium was sufficient to maintain all the contacting germ line cells as GSC-like undifferentiated cells, thus e...

show abstract

Section: Discussionsupporting

confidence: 58%

Novel Contact-dependent Bone Morphogenetic Protein (BMP) Signaling Mediated by Heparan Sulfate Proteoglycans

Dejima

Kanai

Akiyama

et al. 2011

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…HSPGs can also bind to BMP7 and either promote or inhibit signaling (45)(46)(47). Other ECM components or ECM-bound proteins, such as fibronectin, collagen, and members of the crossveinless family, promote BMP signaling through diverse and context-dependent mechanisms (48)(49)(50)(51)(52). The composition of the ECM varies between different tissues and cell types and thus it is feasible that the BMP4 prodomain might be required to facilitate interactions with obligate ECM binding partners present on ectodermal, but not mesodermal cells.…”

Section: Discussionmentioning

confidence: 99%

The prodomain of BMP4 is necessary and sufficient to generate stable BMP4/7 heterodimers with enhanced bioactivity in vivo

Neugebauer¹,

Kwon

Kim³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Bone morphogenetic proteins 4 and 7 (BMP4 and BMP7) are morphogens that signal as either homodimers or heterodimers to regulate embryonic development and adult homeostasis. BMP4/7 heterodimers exhibit markedly higher signaling activity than either homodimer, but the mechanism underlying the enhanced activity is unknown. BMPs are synthesized as inactive precursors that dimerize and are then cleaved to generate both the bioactive ligand and prodomain fragments, which lack signaling activity. Our study reveals a previously unknown requirement for the BMP4 prodomain in promoting heterodimer activity. We show that BMP4 and BMP7 precursor proteins preferentially or exclusively form heterodimers when coexpressed in vivo. In addition, we show that the BMP4 prodomain is both necessary and sufficient for generation of stable heterodimeric ligands with enhanced activity and can enable homodimers to signal in a context in which they normally lack activity. Our results suggest that intrinsic properties of the BMP4 prodomain contribute to the relative bioactivities of homodimers versus heterodimers in vivo. These findings have clinical implications for the use of BMPs as regenerative agents for the treatment of bone injury and disease.B one morphogenetic proteins (BMPs) are members of the TGFβ superfamily that were originally isolated as boneinducing morphogens and were subsequently found to play central roles during embryogenesis and in adult homeostasis (1). BMPs are clinically important therapeutic agents that are used to reverse bone loss caused by trauma, disease, and tumor resection (2). Their use as regenerative agents is limited, however, by their short half-life and low specific activity when implanted in vivo. Understanding how BMP activity is regulated is important for the development of more effective therapeutic agents for the treatment of bone injury and disease.BMPs bind to and activate a receptor complex consisting of type I and type II transmembrane serine/threonine kinases. Following ligand binding, activated receptors propagate their signal by phosphorylating one of the SMADs that is specific for the BMP pathway (SMAD1, -5, or -8). The phosphorylated Smads then form heterooligomers with the common Smad, Smad4, and this complex translocates into the nucleus where it binds to BMP response elements and activates transcription of target genes (1).BMPs are classified into subfamilies based on sequence homology. They signal as either homodimers, or as heterodimers from different subfamilies. For example, class I BMPs, which consist of BMP2 and BMP4, can heterodimerize with class II BMPs, consisting of BMP5-8 (3). Heterodimers composed of distinct BMP family members show a higher specific activity than do homodimers of either subunit. Homodimers of BMP2, -4, or -7, for example, can all induce bone formation, but heterodimers of BMP2 plus BMP7, or BMP4 plus BMP7 are significantly more potent (5-to 20-fold) than any of the homodimers in osteogenic differentiation assays (4-6). BMP2/7 and BMP4/7 heterodimers also sho...

show abstract

“…The ventral side expresses BMP4 and BMP7, Sizzled, and Crossveinless 2 (CV2, also known as Bmper). CV2 binds BMPs and Chordin and has Cysteine-rich BMP-binding domains similar to those of Chordin but remains tethered to the surface of cells in which it is synthesized (34,35).…”

Section: Significancementioning

confidence: 99%

Chordin forms a self-organizing morphogen gradient in the extracellular space between ectoderm and mesoderm in the Xenopus embryo

Plouhinec

Zakin

Moriyama

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

The vertebrate body plan follows stereotypical dorsal-ventral (D-V) tissue differentiation controlled by bone morphogenetic proteins (BMPs) and secreted BMP antagonists, such as Chordin. The three germ layers-ectoderm, mesoderm, and endoderm-are affected coordinately by the Chordin-BMP morphogen system. However, extracellular morphogen gradients of endogenous proteins have not been directly visualized in vertebrate embryos to date. In this study, we improved immunolocalization methods in Xenopus embryos and analyzed the distribution of endogenous Chordin using a specific antibody. Chordin protein secreted by the dorsal Spemann organizer was found to diffuse along a narrow region that separates the ectoderm from the anterior endoderm and mesoderm. This Fibronectin-rich extracellular matrix is called "Brachet's cleft" in the Xenopus gastrula and is present in all vertebrate embryos. Chordin protein formed a smooth gradient that encircled the embryo, reaching the ventral-most Brachet cleft. Depletion with morpholino oligos showed that this extracellular gradient was regulated by the Chordin protease Tolloid and its inhibitor Sizzled. The Chordin gradient, as well as the BMP signaling gradient, was self-regulating and, importantly, was able to rescale in dorsal half-embryos. Transplantation of Spemann organizer tissue showed that Chordin diffused over long distances along this signaling highway between the ectoderm and mesoderm. Chordin protein must reach very high concentrations in this narrow region. We suggest that as ectoderm and mesoderm undergo morphogenetic movements during gastrulation, cells in both germ layers read their positional information coordinately from a single morphogen gradient located in Brachet's cleft.

show abstract

The BMP-Binding Protein Crossveinless 2 Is a Short-Range, Concentration-Dependent, Biphasic Modulator of BMP Signaling in Drosophila

Cited by 155 publications

References 39 publications

Novel Contact-dependent Bone Morphogenetic Protein (BMP) Signaling Mediated by Heparan Sulfate Proteoglycans

Novel Contact-dependent Bone Morphogenetic Protein (BMP) Signaling Mediated by Heparan Sulfate Proteoglycans

The prodomain of BMP4 is necessary and sufficient to generate stable BMP4/7 heterodimers with enhanced bioactivity in vivo

Chordin forms a self-organizing morphogen gradient in the extracellular space between ectoderm and mesoderm in the Xenopus embryo

Contact Info

Product

Resources

About