The function of a Drosophila glypican does not depend entirely on heparan sulfate modification

Kirkpatrick, Catherine; Knox, Sarah M.; Staatz, William D.; Fox, Bethany; Lercher, Daniel; Selleck, Scott B.

doi:10.1016/j.ydbio.2006.09.011

Cited by 93 publications

(96 citation statements)

References 46 publications

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“…As one of our mechanistic questions, we examined whether HS modification is critical for trans signaling. Recent studies have shown that in some in vivo contexts, the activities of glypicans reside in the core protein moiety (24,25). In contrast, our analyses showed that the trans co-receptor activity of DALLY requires its HS modification.…”

Section: Discussioncontrasting

confidence: 59%

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

Dejima

Kanai

Akiyama

et al. 2011

Journal of Biological Chemistry

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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...

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Section: Discussioncontrasting

confidence: 59%

“…Recent studies showed that glypicans retain an unexpected level of activity without modification by glycosaminoglycan sugar chain (24,25).…”

Section: Dally Enhances Dpp Signaling In Drosophila S2mentioning

confidence: 99%

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

Dejima

Kanai

Akiyama

et al. 2011

Journal of Biological Chemistry

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“…In developing Drosophila pupal wings, zebrafish embryos and Xenopus embryos, one of the proposed roles for the BMP-binding protein Crossveinless-2 (Cv-2) is that it regulates the accessibility of ligand to type I receptors (a schematic of the proposed mechanism in Drosophila is shown in figure 1b). The mechanism in figure 1b is a characterization of the proposed action for numerous other regulators, including heparan sulphate proteoglycans (HSPGs) such as Dally [14] and Dally-like [15,16], collagen [17] and others such as BAMBI (bone morphogenetic protein and activin membrane-bound inhibitor) [18]. We refer to the molecules that regulate receptorligand interaction akin to the schematic in figure 1b as surface-associated BMP-binding proteins (SBPs).…”

Section: Introductionmentioning

confidence: 99%

Secreted, receptor-associated bone morphogenetic protein regulators reduce stochastic noise intrinsic to many extracellular morphogen distributions

Karim

Buzzard

Umulis

2011

J. R. Soc. Interface.

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Morphogens are secreted molecules that specify cell-fate organization in developing tissues. Patterns of gene expression or signalling immediately downstream of many morphogens such as the bone morphogenetic protein (BMP) decapentaplegic (Dpp) are highly reproducible and robust to perturbations. This contrasts starkly with our expectation of a noisy interpretation that would arise out of the experimentally determined low concentration (approximately picomolar) range of Dpp activity, tight receptor binding and very slow kinetic rates. To investigate mechanisms by which the intrinsic noise can be attenuated in Dpp signalling, we focus on a class of secreted proteins that bind to Dpp in the extracellular environment and play an active role in regulating Dpp/receptor interactions. We developed a stochastic model of Dpp signalling in Drosophila melanogaster and used the model to quantify the extent that stochastic fluctuations would lead to errors in spatial patterning and extended the model to investigate how a surface-associated BMP-binding protein (SBP) such as Crossveinless-2 (Cv-2) may buffer out signalling noise. In the presence of SBPs, fluctuations in the level of ligand-bound receptor can be reduced by more than twofold depending on parameter values for the intermediate transition states. Regulation of receptor -ligand interactions by SBPs may also increase the frequency of stochastic fluctuations providing a separation of timescales between high-frequency receptor equilibration and slower morphogen patterning. High-frequency noise generated by SBP regulation is easily attenuated by the intracellular network creating a system that imitates the performance of a simple low-pass filter common in audio and communication applications. Together, these data indicate that one of the benefits of receptor-ligand regulation by secreted non-receptors may be greater reliability of morphogen patterning mechanisms.

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“…Such data suggest that HSPG core proteins can function largely as inert and interchangeable scaffolds. However, other evidence suggests that both core proteins and GAG chains may contribute to Hh signaling (see below) and to canonical and noncanonical Wnt signaling (10)(11)(12)(13)(14)(15). For example, loss of GAG modification clearly disrupts Hh ligand movement in Drosophila (9), although a specific requirement for GAG chains or core protein in cell-autonomous response in vivo has not been established.…”

mentioning

confidence: 99%

Dally-like core protein and its mammalian homologues mediate stimulatory and inhibitory effects on Hedgehog signal response

Williams¹,

Pappano²,

Saunders³

et al. 2010

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

103

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The distribution and activities of morphogenic signaling proteins such as Hedgehog (Hh) and Wingless (Wg) depend on heparan sulfate proteoglycans (HSPGs). HSPGs consist of a core protein with covalently attached heparan sulfate glycosaminoglycan (GAG) chains. We report that the unmodified core protein of Dally-like (Dlp), an HSPG required for cell-autonomous Hh response in Drosophila embryos, alone suffices to rescue embryonic Hh signaling defects. Membrane tethering but not specifically the glycosylphosphatidylinositol linkage characteristic of glypicans is critical for this cell-autonomous activity. Our studies further suggest divergence of the two Drosophila and six mammalian glypicans into two functional families, an activating family that rescues cell-autonomous Dlp function in Hh response and a family that inhibits Hh response. Thus, in addition to the previously established requirement for HSPG GAG chains in Hh movement, these findings demonstrate a positive cell-autonomous role for a core protein in morphogen response in vivo and suggest the conservation of a network of antagonistic glypican activities in the regulation of Hh response.

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The function of a Drosophila glypican does not depend entirely on heparan sulfate modification

Cited by 93 publications

References 46 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

Secreted, receptor-associated bone morphogenetic protein regulators reduce stochastic noise intrinsic to many extracellular morphogen distributions

Dally-like core protein and its mammalian homologues mediate stimulatory and inhibitory effects on Hedgehog signal response

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