A mouse model of juvenile hemochromatosis

Huang, Franklin W.; Pinkus, Jack L.; Pinkus, Geraldine S.; Fleming, Mark D.; Andrews, Nancy C.

doi:10.1172/jci25049

Cited by 324 publications

(328 citation statements)

References 33 publications

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“…Mice homozygous for strong hypomorphic Ntn1 (encoding netrin-1) alleles are not reported to have defects in muscle development (Serafini et al, 1996;Salminen et al, 2000), and Hfe2 (encoding RGMc)-null mice are reported to have normal muscle development (Huang et al, 2005;Niederkofler et al, 2005). Mice lacking netrin-3 have not been generated.…”

Section: Discussionmentioning

confidence: 99%

“…Mice lacking netrin-3 have not been generated. Netrin-2 (the chick family member most closely related to mammalian netrin-3) promoted C2C12 myotube formation in a neogenin-dependent manner, whereas stable overexpression of RGMc in C2C12 cells was reported to have no effect on myotube formation (Huang et al, 2005;Niederkofler et al, 2005;Kuninger et al, 2006). Furthermore, netrin-2 stimulated FAK and ERK activation in Neo1 ϩ/ϩ , but not Neo1 Gt/Gt , myoblasts in vitro; in contrast, RGMc displayed lesser ability to do so, though the levels of phospho-FAK and phospho-ERK were generally a bit higher in wild-type than mutant cells in the presence of RGMc.…”

Section: Discussionmentioning

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: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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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“…Although mutations in HJV in juvenile hemochromatosis patients and deletion of HJV in mice resulted in abnormally low hepcidin expression (20), it is unlikely that the interaction between HJV and neogenin is directly involved in regulating hepcidin levels. Instead, recent findings demonstrating that HJV binds some BMPs and that incubation of hepatocytes with exogenous BMP-2 upregulates hepcidin expression (26) suggest a more direct role for the HJV-BMP interaction in regulating hepcidin.…”

Section: Discussionmentioning

confidence: 99%

Neogenin Interacts with Hemojuvelin through Its Two Membrane-Proximal Fibronectin Type III Domains

et al. 2008

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Hemojuvelin is a recently identified iron-regulatory protein that plays an important role in affecting the expression of hepcidin, a key iron regulatory hormone. Although the underlying mechanism of this process is not clear, several hemojuvelin-binding proteins, including the cell surface receptor neogenin and bone morphogenetic protein (BMP) cytokines, have been identified. The ectodomain of neogenin is composed of four immunoglobulin-like (Ig) domains followed by six fibronectin type III-like (FNIII) domains. Here we report expression of soluble versions of hemojuvelin and neogenin for biochemical characterization of their interaction and the interaction of HJV with BMP-2. Hemojuvelin normally undergoes an autocatalytic cleavage, and as in ViVo, recombinant hemojuvelin exists as a mixture of cleaved and uncleaved forms. Neogenin binds to cleaved and noncleaved hemojuvelin, as verified by its binding to an uncleaved mutant hemojuvelin. We localized the hemojuvelin binding site on neogenin to the membrane-proximal fifth and sixth FNIII domains and the juxtamembrane linker and showed that a fragment containing only this region binds 2-3 orders of magnitude more tightly than the entire neogenin ectodomain. Binding to the most membrane-proximal region of neogenin may play a role in regulating the levels of soluble and membrane-bound forms of hemojuvelin, which in turn would influence the amount of free BMP-2 available for binding to its receptors and triggering transcription of the hepcidin gene. Our finding that BMP-2 and neogenin bind simultaneously to hemojuvelin raises the possibility that neogenin is part of a multiprotein complex at the hepatocyte membrane involving BMP, its receptors, and hemojuvelin.

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“…These observations suggest that other unidentified factors may participate along with IRPs in cellular iron homeostasis (Hentze et al, 2004). In mouse, a model of hereditary hemochromatosis was developed, which is an iron-overload disorder resulting from mutations in hemojuvelin, a protein involved in the maintenance of iron homeostasis (Huang et al, 2005).…”

Section: Common Methods Used In Fe Metabolismmentioning

confidence: 99%

Advantages and disadvantages of the animal models v. in vitro studies in iron metabolism: a review

García¹,

Díaz-Castro

2013

Animal

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Iron deficiency is the most common nutritional deficiency in the world. Special molecules have evolved for iron acquisition, transport and storage in soluble, nontoxic forms. Studies about the effects of iron on health are focused on iron metabolism or nutrition to prevent or treat iron deficiency and anemia. These studies are focused in two main aspects: (1) basic studies to elucidate iron metabolism and (2) nutritional studies to evaluate the efficacy of iron supplementation to prevent or treat iron deficiency and anemia. This paper reviews the advantages and disadvantages of the experimental models commonly used as well as the methods that are more used in studies related to iron. In vitro studies have used different parts of the gut. In vivo studies are done in humans and animals such as mice, rats, pigs and monkeys. Iron metabolism is a complex process that includes interactions at the systemic level. In vitro studies, despite physiological differences to humans, are useful to increase knowledge related to this essential micronutrient. Isotopic techniques are the most recommended in studies related to iron, but their high cost and required logistic, making them difficult to use. The depletion--repletion of hemoglobin is a method commonly used in animal studies. Three depletion--repletion techniques are mostly used: hemoglobin regeneration efficiency, relative biological values (RBV) and metabolic balance, which are official methods of the association of official analytical chemists. These techniques are well-validated to be used as studies related to iron and their results can be extrapolated to humans. Knowledge about the main advantages and disadvantages of the in vitro and animal models, and methods used in these studies, could increase confidence of researchers in the experimental results with less costs.

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A mouse model of juvenile hemochromatosis

Cited by 324 publications

References 33 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 Interacts with Hemojuvelin through Its Two Membrane-Proximal Fibronectin Type III Domains

Advantages and disadvantages of the animal models v. in vitro studies in iron metabolism: a review

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