Expression Studies of Neogenin and Its Ligand Hemojuvelin in Mouse Tissues

Rodríguez, Alejandra; Pan, Pei; Parkkila, Seppo

doi:10.1369/jhc.6a7031.2006

Cited by 32 publications

(42 citation statements)

References 27 publications

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“…Neo1 is expressed in fetal premuscle masses and adult muscle Fitzgerald et al, 2006;Rodriguez et al, 2007) and, as shown here, developing somites. However, although Neo1 Gt/Gt mice displayed an obvious defect in the formation of fully sized myofibers, they did not show a defect in the formation of myotomes.…”

Section: Discussionsupporting

confidence: 75%

“…Defective Skeletal Muscle Development in Neo1 Gt/Gt Mice Neogenin mRNA and protein are expressed prominently in E14.5 fetal mouse muscle masses and in adult muscle Fitzgerald et al, 2006;Rodriguez et al, 2007). However, little information exists on Neo1 expression during earlier stages of myogenesis.…”

Section: The Neo1 Gt Allele Is Hypomorphic and Results In Incompletelmentioning

confidence: 99%

“…Furthermore, vascular smooth muscle cells are attracted by and adhere to netrin-1 in a neogenin-dependent manner . Neogenin morphant zebrafish display an aberrant neural tube and defects in somitogenesis, suggesting possible roles in convergent extension and/or cell polarity during formation of the rostrocaudal axis (Mawdsley et al, 2004).Neogenin is expressed throughout the developing mouse embryo but is at high levels in developing skeletal muscle; netrin-1, netrin-3, and RGMc are also expressed in premuscle masses of the mouse embryo Keeling et al, 1997;Wang et al, 1999;Kuninger et al, 2004;Niederkofler et al, 2004;Fitzgerald et al, 2006;Rodriguez et al, 2007). We recently showed that mouse myoblast cell lines and cultured primary myoblasts derived from satellite cells express netrin-3 and neogenin and that these factors promote formation of multinucleated myotubes .…”

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confidence: 99%

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Neogenin Regulates Skeletal Myofiber Size and Focal Adhesion Kinase and Extracellular Signal-regulated Kinase Activities In Vivo and In Vitro

Bae

Yang

Jiang

et al. 2009

MBoC

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A variety of signaling pathways participate in the development of skeletal muscle, but the extracellular cues that regulate such pathways in myofiber formation are not well understood. Neogenin is a receptor for ligands of the netrin and repulsive guidance molecule (RGM) families involved in axon guidance. We reported previously that neogenin promoted myotube formation by C2C12 myoblasts in vitro and that the related protein Cdo (also Cdon) was a potential neogenin coreceptor in myoblasts. We report here that mice homozygous for a gene-trap mutation in the Neo1 locus (encoding neogenin) develop myotomes normally but have small myofibers at embryonic day 18.5 and at 3 wk of age. Similarly, cultured myoblasts derived from such animals form smaller myotubes with fewer nuclei than myoblasts from control animals. These in vivo and in vitro defects are associated with low levels of the activated forms of focal adhesion kinase (FAK) and extracellular signal-regulated kinase (ERK), both known to be involved in myotube formation, and inefficient expression of certain muscle-specific proteins. Recombinant netrin-2 activates FAK and ERK in cultured myoblasts in a neogenin-and Cdo-dependent manner, whereas recombinant RGMc displays lesser ability to activate these kinases. Together, netrin-neogenin signaling is an important extracellular cue in regulation of myogenic differentiation and myofiber size. INTRODUCTIONSkeletal muscle is the most abundant tissue, by mass, in the vertebrate body. Muscles of the trunk and limbs arise from the somites, with myogenic progenitor cells derived from the dorsal region of the maturing somite, the dermomyotome (Tajbakhsh and Buckingham, 2000;Pownall et al., 2002;Charge and Rudnicki, 2004). In response to signals from the adjacent notochord, neural tube, and surface ectoderm, some dermomyotomal progenitors become committed to the muscle lineage and form the myotome, a set of differentiated muscle cells that underlies the dermomyotome. Subsequent embryonic, fetal, and postnatal stages of myogenesis are thought to involve additional muscle progenitors that migrate from the dermomyotome and ultimately establish the trunk and limb musculature, as well as satellite cells, adult muscle precursor cells (Gros et al., 2005;Kassar-Duchossoy et al., 2005;Relaix et al., 2005). Somitic progenitor cells are specified to become muscle lineage-committed myoblasts through the action of the myogenic basic helix-loop-helix transcription factors Myf5, MRF4, and MyoD, whereas differentiation of myoblasts is regulated by myogenin, MyoD, and MRF4 (Tajbakhsh, 2005). These and other transcription factors coordinate the process of differentiation, including cell cycle withdrawal, expression of muscle-specific proteins, cellular elongation, and fusion into multinucleated myofibers. Although transcriptional regulation is at the core of myogenesis, the formation and growth of myofibers is also controlled by a variety of signaling ligands and their receptors, including insulin-like growth factor-1, fibroblast growth fac...

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Section: Discussionsupporting

confidence: 75%

Section: The Neo1 Gt Allele Is Hypomorphic and Results In Incompletelmentioning

confidence: 99%

mentioning

confidence: 99%

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Neogenin Regulates Skeletal Myofiber Size and Focal Adhesion Kinase and Extracellular Signal-regulated Kinase Activities In Vivo and In Vitro

Bae

Yang

Jiang

et al. 2009

MBoC

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“…by guest www.bloodjournal.org From abundantly in liver and skeletal muscles, consistent with previous reports. 38 Intriguingly, HJV protein in neogenin mutant liver and muscle was significantly reduced (Figure 6A), suggesting a role for neogenin in HJV expression or stability. RT-PCR analysis of P20 muscle RNA demonstrated no difference at HJV mRNA levels between wild-type and mutant mice ( Figure 6B), suggesting that neogenin regulation is posttranscriptional.…”

Section: Neogenin Regulation Of Hjv Protein Level and Distributionmentioning

confidence: 94%

Neogenin inhibits HJV secretion and regulates BMP-induced hepcidin expression and iron homeostasis

Lee

Zhou

et al. 2010

Blood

115

105

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Neogenin, a deleted in colorectal cancer (DCC) family member, has been identified as a receptor for the neuronal axon guidance cues netrins and repulsive guidance molecules repulsive guidance molecules (RGM). RGMc, also called hemojuvelin (HJV), is essential for iron homeostasis. Here we provide evidence that neogenin plays a critical role in iron homeostasis by regulation of HJV secretion and bone morphogenetic protein (BMP) signaling.Livers of neogenin mutant mice exhibit iron overload, low levels of hepcidin, and reduced BMP signaling. Mutant hepatocytes in vitro show impaired BMP2 induction of Smad1/5/8 phosphorylation and hepcidin expression. Neogenin is expressed in liver cells in a reciprocal pattern to that of hepcidin, suggesting that neogenin functions in a cell nonautonomous manner. Further studies demonstrate that neogenin may stabilize HJV, a glycosylphosphatidylinositol-anchored protein that interacts with neogenin and suppresses its secretion. Taken together, our results lead the hypothesis that neogenin regulates iron homeostasis via inhibiting secretion of HJV, an inhibitor of BMP signaling, to enhance BMP signaling and hepcidin expression. These results reveal a novel mechanism underlying neogenin regulation of HJV-BMP signaling. IntroductionIron, a component of many metalloproteins, plays a crucial role in various physiologic processes, such as oxygen sensing and transport, mitochondrial electron transfer in the respiratory chain, and catalytic activity of diverse enzymes. Dysregulation of iron homeostasis leads to either iron deficiency, such as anemia, or iron overload characteristic of hereditary hemochromatosis, a relatively common inherited disorder associated with progressive organ dysfunction. 1 Cellular iron overload is toxic and causes cell death, at least in part due to free radical formation and lipid peroxidation.Hemojuvelin (HJV) is a member of a family of glycosylphosphatidylinositol (GPI)-linked cell surface proteins. It has an essential role in iron homeostasis. 2 HJV contains a putative N-terminal signal peptide, a tri-amino acid motif (the RGD site), a partial von Willebrand factor type D domain, and a C-terminal GPI anchor consensus sequence. 2,3 It is predominately expressed in the skeletal muscle, heart, and liver. 3,4 Mutations in the HJV gene is a leading cause of juvenile hemochromatosis, [5][6][7][8] and patients have low levels of hepcidin, 5,8 a crucial hormone secreted by the liver for iron homeostasis. HJV mutant mice exhibit reduced hepcidin expression and iron overload, 5,6 resembling patients with HJV mutations. Consistently, expression of HJV increases, while suppression of HJV decreases, hepcidin expression in cultured cells. 9 The mechanisms underlying HJV regulation of hepcidin expression and iron homeostasis are beginning to be elucidated. HJV was shown to function as a coreceptor for bone morphogenetic proteins (BMP). It binds to BMP2/4/6 and forms a complex with BMP receptors (type I and II). 10-12 HJV deficient mice/cells exhibit impaired BMP signaling ...

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“…RGMc is expressed in skeletal muscle, heart, liver, bone, and cartilage (Samad et al, 2004;Niederkofler et al, 2004;Papanikolaou et al, 2004;Rodriguez et al, 2007;Kanomata et al, 2009), but its function in these tissues remains largely unknown. Nevertheless, mutations of RGMc have been linked with Hereditary Hemochromatosis, a heterogeneous group of autosomal recessive diseases that cause increased intestine absorption and deposition of iron in heart, liver, endocrine glands, joints, and skin (revised by Pietrangelo, 2007).…”

Section: Introductionmentioning

confidence: 99%

RGMa and RGMb expression pattern during chicken development suggest unexpected roles for these repulsive guidance molecules in notochord formation, somitogenesis, and myogenesis

Jorge

Ahmed

Bothe

et al. 2012

Developmental Dynamics

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Background: Repulsive guidance molecules (RGM) are high-affinity ligands for the Netrin receptor Neogenin, and they are crucial for nervous system development including neural tube closure; neuronal and neural crest cell differentiation and axon guidance. Recent studies implicated RGM molecules in bone morphogenetic protein signaling, which regulates a variety of developmental processes. Moreover, a role for RGMc in iron metabolism has been established. This suggests that RGM molecules may play important roles in non-neural tissues. Results: To explore which tissues and processed may be regulated by RGM molecules, we systematically investigated the expression of RGMa and RGMb, the only RGM molecules currently known for avians, in the chicken embryo. Conclusions: Our study suggests so far unknown roles of RGM molecules in notochord, somite and skeletal muscle development. Developmental Dynamics 241: [1886][1887][1888][1889][1890][1891][1892][1893][1894][1895][1896][1897][1898][1899][1900] 2012. V C 2012 Wiley Periodicals, Inc.Key words: RGMa; DRAGON; RGMb; chicken; embryo; neural plate, neurogenesis; dorsal root ganglia; pharyngeal ectoderm; notochord; somite; dermomyotome; myotome Key findings:RGMa and RGMb expression patterns in neural tissues are conserved in gnathostome vertebrates. RGMa might be associated with muscle stem cells capable of undertaking myogenesis, and RGMb with cells ready to enter myogenic differentiation. Developmental DynamicsABBREVIATIONS asp anterior segmental plate di diencephalon dm dermomyotome dml dorsomedial lip of the dermomyotome drg dorsal root ganglion ect ectoderm edl Extensor Digitorum Longus end endoderm f fibula bone fge foregut endoderm fp floor plate of the neural tube hm head mesoderm hy hyoid (2nd) pharyngeal arch m myotome ma mandibular (1st) pharyngeal arch mes mesencephalon mx maxillary aspect of the 1st pharyngeal arch myel myelencephalon node Hensen's node (avian organizer) not notochord np neural plate nt neural tube op otic placode os optic stalk ov otic vesicle pa pharyngeal arch pchpl prechordal plate p/not posterior notochord ps primitive streak r1 r2 etc rhombomere 1 rhombomere 2 etc. s0 epithelializing somite s1 s5 etc 1st somite 5th somite etc. t tibiotarsal bone tel telencephalon V trigeminal (5th cranial nerve) ganglion VII facial (7th cranial nerve) ganglion vll ventromedial lip of the dermomyotome.Additional Supporting information may be found in the online version of this article.

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Expression Studies of Neogenin and Its Ligand Hemojuvelin in Mouse Tissues

Cited by 32 publications

References 27 publications

Neogenin Regulates Skeletal Myofiber Size and Focal Adhesion Kinase and Extracellular Signal-regulated Kinase Activities In Vivo and In Vitro

Neogenin Regulates Skeletal Myofiber Size and Focal Adhesion Kinase and Extracellular Signal-regulated Kinase Activities In Vivo and In Vitro

Neogenin inhibits HJV secretion and regulates BMP-induced hepcidin expression and iron homeostasis

RGMa and RGMb expression pattern during chicken development suggest unexpected roles for these repulsive guidance molecules in notochord formation, somitogenesis, and myogenesis

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