Bone morphogenetic proteins (BMPs) are members of the transforming growth factor β (TGF-β) superfamily of ligands, which regulate
many mammalian physiologic and pathophysiologic processes. BMPs exert their effects through type I and type II serine/threonine
kinase receptors and the Smad intracellular signaling pathway. Recently, the glycosylphosphatidylinositol (GPI)-anchored protein
DRAGON was identified as a co-receptor for BMP signaling. Here, we investigate whether a homologue of DRAGON, repulsive guidance
molecule (RGMa), is similarly involved in the BMP signaling pathway. We show that RGMa enhances BMP, but not TGF-β, signals
in a ligand-dependent manner in cell culture. The soluble extracellular domain of RGMa fused to human Fc (RGMa.Fc) forms a
complex with BMP type I receptors and binds directly and selectively to radiolabeled BMP-2 and BMP-4. RGMa mediates BMP signaling
through the classical BMP signaling pathway involving Smad1, 5, and 8, and it up-regulates endogenous inhibitor of differentiation
(Id1) protein, an important downstream target of BMP signals. Finally, we demonstrate that BMP signaling occurs in neurons
that express RGMa in vivo. These data are consistent with a role for RGMa as a BMP co-receptor.
"A breakthrough in understanding the mechanism of action of HJV in hepcidin regulation came when HJV was discovered to function as a co-receptor for the bone morphogenetic protein (BMP) signaling pathway (Babitt et al., 2006), analogous to its RGM family homologs (Babitt et al., 2005; Samad et al., 2005). Importantly, this BMP signaling function of HJV was demonstrated to be crucial for its role in regulating hepcidin expression (Babitt et al., 2006) (Figure 1). "
[Show abstract][Hide abstract] ABSTRACT: Mutations in hemojuvelin (HJV) are the most common cause of the juvenile-onset form of the iron overload disorder hereditary hemochromatosis. The discovery that HJV functions as a co-receptor for the bone morphogenetic protein (BMP) family of signaling molecules helped to identify this signaling pathway as a central regulator of the key iron hormone hepcidin in the control of systemic iron homeostasis. This review highlights recent work uncovering the mechanism of action of HJV and the BMP-SMAD signaling pathway in regulating hepcidin expression in the liver, as well as additional studies investigating possible extra-hepatic functions of HJV. This review also explores the interaction between HJV, the BMP-SMAD signaling pathway and other regulators of hepcidin expression in systemic iron balance.
Frontiers in Pharmacology 05/2014; 5:104. DOI:10.3389/fphar.2014.00104 · 3.80 Impact Factor
"Yet it is not known which, if any, of these RGMa-mediated processes is due to the potentiation of BMP signaling by RGMa. For example, BMP signaling occurs in neurons of the mouse adult spinal cord that expresses RGMa (Babitt et al., 2005), however it is not known if RGMa functions by mediating BMP signaling there. Many of the processes that RGMa is involved in require the function of the RGM receptor neogenin (discussed more later), but despite their overlapping expression patterns in some tissues, it is not known if both proteins function together via BMP signaling to regulate these processes in vivo. "
"Interactions between RGMs and Neogenin are required for both the neuronal and non-neuronal functions of RGMa and RGMb, including their neurite growth inhibitory and axon repulsive effects , , , –. In addition, RGMs and also Neogenin interact with bone morphogenetic proteins (BMPs) and their receptors, but thus far RGM-mediated modulation of BMP signaling has not been implicated in the neurodevelopmental functions of RGMs , –. Binding of RGMa or RGMb to Neogenin on neuronal growth cones leads to activation of the Rho kinase pathway and inactivation of Ras signaling , , . Interestingly, activation of RhoA by RGMs is dependent on another family of Netrin-1 receptors, Unc5s . "
[Show abstract][Hide abstract] ABSTRACT: Neogenin has been implicated in a variety of developmental processes such as neurogenesis, neuronal differentiation, apoptosis, migration and axon guidance. Binding of repulsive guidance molecules (RGMs) to Neogenin inhibits axon outgrowth of different neuronal populations. This effect requires Neogenin to interact with co-receptors of the uncoordinated locomotion-5 (Unc5) family to activate downstream Rho signaling. Although previous studies have reported RGM, Neogenin, and/or Unc5 expression, a systematic comparison of RGM and Neogenin expression in the developing nervous system is lacking, especially at later developmental stages. Furthermore, information on RGM and Neogenin expression at the protein level is limited. To fill this void and to gain further insight into the role of RGM-Neogenin signaling during mouse neural development, we studied the expression of RGMa, RGMb, Neogenin and Unc5A-D using hybridization, immunohistochemistry and RGMa section binding. Expression patterns in the primary olfactory system, cortex, hippocampus, habenula, and cerebellum were studied in more detail. Characteristic cell layer-specific expression patterns were detected for RGMa, RGMb, Neogenin and Unc5A-D. Furthermore, strong expression of RGMa, RGMb and Neogenin protein was found on several major axon tracts such as the primary olfactory projections, anterior commissure and fasciculus retroflexus. These data not only hint at a role for RGM-Neogenin signaling during the development of different neuronal systems, but also suggest that Neogenin partners with different Unc5 family members in different systems. Overall, the results presented here will serve as a framework for further dissection of the role of RGM-Neogenin signaling during neural development.
PLoS ONE 02/2013; 8(2):e55828. DOI:10.1371/journal.pone.0055828 · 3.23 Impact Factor
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