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A Skeleton in the Closet: Neogenin Guides Bone Development

2010; Elsevier BV; Volume: 19; Issue: 1 Linguagem: Inglês

10.1016/j.devcel.2010.07.004

1878-1551

Monika Podkowa, Liliana Attisano,

Hedgehog Signaling Pathway Studies

Bone Morphogenetic Proteins (BMPs) are key regulators of skeletal development. In this issue of Developmental Cell, Zhou et al. show that neogenin, a receptor for neuronal axon guidance, also regulates endochondral bone formation and BMP signaling and does so by influencing BMP receptor localization in membrane microdomains. Bone Morphogenetic Proteins (BMPs) are key regulators of skeletal development. In this issue of Developmental Cell, Zhou et al. show that neogenin, a receptor for neuronal axon guidance, also regulates endochondral bone formation and BMP signaling and does so by influencing BMP receptor localization in membrane microdomains. The formation of long bones during skeletal development occurs by endochondral ossification, in which the embryonic cartilage template is replaced by bone in an intricate process involving chondrocyte proliferation, hypertrophy, and apoptosis (Kronenberg, 2003Kronenberg H.M. Nature. 2003; 423: 332-336Crossref PubMed Scopus (2144) Google Scholar). The cartilage extracellular matrix, formed by chondrocytes, is then invaded by blood vessels, osteoclasts, bone marrow cells, and osteoblasts that deposit and continuously remodel mineralized bone. This process is tightly regulated by a plethora of extracellular factors, including parathyroid hormone related protein (PTHrP), Indian hedgehog (Ihh), fibroblast growth factor (FGF), Wnts, and Bone Morphogenetic Proteins (BMPs) (Kronenberg, 2003Kronenberg H.M. Nature. 2003; 423: 332-336Crossref PubMed Scopus (2144) Google Scholar). BMPs are members of the Transforming Growth Factor β (TGFβ) superfamily and are key regulators of bone formation. In the BMP Smad pathway, BMP type I and type II serine/threonine kinase receptors recruit and phosphorylate receptor-regulated Smad transcriptional modulators (R-Smad1, 5, and 8). These activated R-Smads form a complex with Smad4 and accumulate in the nucleus, where they regulate gene transcription (Attisano and Wrana, 2002Attisano L. Wrana J.L. Science. 2002; 296: 1646-1647Crossref PubMed Scopus (1133) Google Scholar, Moustakas and Heldin, 2009Moustakas A. Heldin C.H. Development. 2009; 136: 3699-3714Crossref PubMed Scopus (687) Google Scholar). As implied by their moniker, BMPs have a long and storied history in the field of bone development. BMPs are master regulators of chondrogenesis and osteoblastogenesis, and mutations in either BMPs or their receptors result in aberrant chondrogenesis in mice (Song et al., 2009Song B. Estrada K.D. Lyons K.M. Cytokine Growth Factor Rev. 2009; 20: 379-388Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar). Now enter neogenin, a member of the Deleted in Colorectal Cancer (DCC) family of axon guidance receptors. Neogenin binds netrins and Repulsive Guidance Molecules (RGMs) to regulate neuronal morphogenesis, functions that would seem far removed from bone (Cole et al., 2007Cole S.J. Bradford D. Cooper H.M. Int. J. Biochem. Cell Biol. 2007; 39: 1569-1575Crossref PubMed Scopus (59) Google Scholar, De Vries and Cooper, 2008De Vries M. Cooper H.M. J. Neurochem. 2008; 106: 1483-1492Crossref PubMed Scopus (84) Google Scholar). However, in this issue of Developmental Cell, Zhou et al. report the surprising finding that neogenin is required for BMP signaling during chondrogenesis and skeletal development (Zhou et al., 2010Zhou Z. Xie J. Lee D. Liu Y. Jung J. Zhou L. Xiong S. Mei L. Xiong W.-C. Dev. Cell. 2010; 19 (this issue): 90-102Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar). Intriguingly, they show that neogenin mutant mice display defects in digit and limb development and endochondral ossification with reduced chondrocyte hypertrophy, angiogenesis, and osteoblast invasion. Chondrocytes isolated from neogenin mutant mice exhibited reduced matrix deposition, impaired chondrocyte differentiation, and defective expression of several genes associated with chondrocyte maturation. As mentioned above, BMPs play a key role in skeletal development, and focused analysis revealed that neogenin-deficient chondrocytes display reduced expression of BMP target genes and defective BMP2-induced activation of the R-Smad intracellular signaling mediators, both in cultured cells and in mice. These results reveal a critical role for neogenin in promoting chondrogenesis in vitro and in vivo, and uncover a novel and unexpected role for neogenin in the regulation of BMP signaling during skeletal development. Regulation of BMP signaling by neogenin is not as far-fetched as it may first appear. As a member of the netrin-binding DCC family, neogenin first received attention for its role as a netrin receptor that functions in axon guidance (Cole et al., 2007Cole S.J. Bradford D. Cooper H.M. Int. J. Biochem. Cell Biol. 2007; 39: 1569-1575Crossref PubMed Scopus (59) Google Scholar, De Vries and Cooper, 2008De Vries M. Cooper H.M. J. Neurochem. 2008; 106: 1483-1492Crossref PubMed Scopus (84) Google Scholar). However, neogenin also binds members of the RGM family (Severyn et al., 2009Severyn C.J. Shinde U. Rotwein P. Biochem. J. 2009; 422: 393-403Crossref PubMed Scopus (50) Google Scholar). RGMs are glycosylphosphatidylinositol (GPI)-anchored proteins composed of three members: RGMa, RGMb (or DRAGON), and RGMc (or hemojuvelin/hemochromatosis type 2; HFE2). Each RGM displays a distinct pattern of expression, and though the physiological functions are not yet fully understood, it is known that the RGM biological repertoire includes repulsive axon guidance, neuronal survival, and in the case of RGMc, the regulation of systemic iron metabolism (Severyn et al., 2009Severyn C.J. Shinde U. Rotwein P. Biochem. J. 2009; 422: 393-403Crossref PubMed Scopus (50) Google Scholar). Neogenin has been implicated in several of these RGM-mediated pathways, but of particular interest here, RGMs have been directly linked to BMP signaling. Indeed, RGMb was shown to directly bind certain BMPs, to associate with BMP type I and type II receptors, and to increase cell responsiveness to BMPs (Samad et al., 2005Samad T.A. Rebbapragada A. Bell E. Zhang Y. Sidis Y. Jeong S.J. Campagna J.A. Perusini S. Fabrizio D.A. Schneyer A.L. et al.J. Biol. Chem. 2005; 280: 14122-14129Crossref PubMed Scopus (185) Google Scholar), an observation that has now been extended to other RGM family members (Severyn et al., 2009Severyn C.J. Shinde U. Rotwein P. Biochem. J. 2009; 422: 393-403Crossref PubMed Scopus (50) Google Scholar). The work from Zhou et al. nicely dovetails with these prior studies. Specifically, the authors show that RGMs, which interact with both neogenin and BMP receptors, act as protein bridges that lead to the formation of a BMP receptor supercomplex consisting of BMP receptors, RGMs, and neogenin. So, what is the purpose of this supercomplex? Cell plasma membranes are composed of membrane microdomains or lipid rafts that are thought to serve as platforms to segregate membrane components and thereby control various physiological processes, including signal transduction (Simons and Toomre, 2000Simons K. Toomre D. Nat. Rev. Mol. Cell Biol. 2000; 1: 31-39Crossref PubMed Scopus (5155) Google Scholar). Analysis of neogenin-deficient chondrocytes by Zhou et al. revealed that the levels of BMP receptors in lipid rafts were diminished, and that this paralleled a reduction in R-Smad activation. This would indicate that optimal Smad activation requires the localization of BMP receptors in lipid rafts. Thus, Zhou et al. propose an exciting model wherein neogenin facilitates BMP/Smad signaling by enhancing lipid raft localization of BMP receptors and RGMs provide the physical link between neogenin and the BMP receptors (Figure 1). One key question now is how neogenin promotes RGM and BMP receptor localization into lipid raft compartments. One possibility is that the interaction between RGMs and BMP receptors in lipid rafts may be stabilized by neogenin and thus lead to enhanced BMP signaling. Neogenin might also be required for directing RGMs and BMP receptors into lipid rafts. Although Smad activation required neogenin, the authors report that Smad-independent, BMP-induced activation of p38 MAPK did not. An understanding of the molecular basis for this difference will also require future attention. Neogenin is a multifunctional receptor binding both netrins and RGMs, yet signaling pathways activated by neogenin are poorly understood. The novel role of neogenin in promoting lipid raft localization of RGMs and BMP receptors during endochondral bone formation reveals an additional layer of complexity of neogenin-mediated signaling and raises additional intriguing questions. In addition to BMP receptors, does neogenin recruit other protein partners into lipid rafts to regulate neuronal or nonneuronal cell activities? How ubiquitous is the requirement for neogenin in the multitude of known BMP-dependent processes? Do the pathways that neogenin regulates in skeletal development also act in axon guidance? This study provides an important advance that has opened up numerous exciting avenues for future investigation, which will undoubtedly help unravel the mysteries of BMP signaling and neogenin.