Craniofacial defects in mice lacking BMP type I receptor Alk2 in neural crest cells

Dudáš, Marek; Sridurongrit, Somyoth; Nagy, Andre; Okazaki, Kenji; Kaartinen, Vesa

doi:10.1016/j.mod.2003.12.003

Cited by 195 publications

(208 citation statements)

References 30 publications

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“…These mouse models do, however, shed light on the mechanisms involved in craniofacial neural crest lesions. Mice lacking the ET A receptor for endothelin-1 (Et-1) or the Alk2 receptor for bone morphogenic protein (Bmp) display craniofacial defects similar to those reported for the diabetic mice (Clouthier et al, 1998;Dudas et al, 2004).…”

Section: Discussionmentioning

confidence: 83%

Reduction in diabetes‐induced craniofacial defects by maternal immune stimulation

Hrubec

Prater

Toops

et al. 2005

Birth Defects Research Pt B

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BACKGROUND: Maternal diabetes can induce a number of developmental abnormalities in laboratory animals and humans, including facial deformities and defects in neural tube closure. The incidence of birth defects in newborns of diabetic women is approximately 3–5 times higher than among non‐diabetics. In mice, non‐specific activation of the maternal immune system can reduce fetal abnormalities caused by diverse etiologies, including diabetes induced neural tube defects. This study was conducted to determine whether non‐specific maternal immune stimulation could reduce diabetes‐induced craniofacial defects as well. METHODS: Maternal immune function was stimulated before streptozocin (STZ) treatment by maternal footpad injection with Freund's complete adjuvant (FCA), maternal intraperitoneal (i.p.) injection with granulocyte‐macrophage colony‐stimulating factor (GM‐CSF), or maternal i.p. injection with interferon‐γ (IFNγ). Streptozocin (200 mg/kg i.p.) was used to induce hyperglycemia (26–35 mmol blood glucose) in female ICR mice before breeding. Fetuses from 12–18 litters per treatment group, were collected at Day 17 of gestation. RESULTS: Craniofacial defects were observed in fetuses from all hyperglycemic groups. The incidence of defects was significantly decreased in fetuses from dams immune stimulated with IFNγ or GM‐CSF. The most common defects were reduced maxillary and mandibular lengths. Both were prevented by maternal stimulation with GM‐CSF. CONCLUSION: Maternal immune stimulation reduced the incidence of diabetic craniofacial embryopathy. The mechanisms for these protective effects are unknown but may involve maternal or fetal production of cytokines or growth factors that protect the fetus from the dysregulatory effects of hyperglycemia. Birth Defects Res Part B 2006. © 2005 Wiley‐Liss, Inc.

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Section: Discussionmentioning

confidence: 83%

Reduction in diabetes‐induced craniofacial defects by maternal immune stimulation

Hrubec

Prater

Toops

et al. 2005

Birth Defects Research Pt B

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“…BMP signaling regulates specification and migration of cranial neural crest cells to the facial primordia (reviewed in Nie et al 2006), and also controls mesenchymal cell proliferation. Tissue-specific inhibition of this signaling pathway by conditional inactivating mutations in BMP receptors or overexpression of the antagonist noggin causes a reduced proliferation rate within the palatal mesenchyme and results in palate clefting (Dudas et al 2004;Liu et al 2005;He et al 2010;Baek et al 2011). …”

Section: Digit Malformations Caused By Disruption Of Tgf-b and Bmp Simentioning

confidence: 99%

TGF-β Family Signaling in Connective Tissue and Skeletal Diseases

MacFarlane

Haupt

Dietz

et al. 2017

Cold Spring Harb Perspect Biol

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The transforming growth factor b (TGF-b) family of signaling molecules, which includes TGF-bs, activins, inhibins, and numerous bone morphogenetic proteins (BMPs) and growth and differentiation factors (GDFs), has important functions in all cells and tissues, including soft connective tissues and the skeleton. Specific TGF-b family members play different roles in these tissues, and their activities are often balanced with those of other TGF-b family members and by interactions with other signaling pathways. Perturbations in TGF-b family pathways are associated with numerous human diseases with prominent involvement of the skeletal and cardiovascular systems. This review focuses on the role of this family of signaling molecules in the pathologies of connective tissues that manifest in rare genetic syndromes (e.g., syndromic presentations of thoracic aortic aneurysm), as well as in more common disorders (e.g., osteoarthritis and osteoporosis). Many of these diseases are caused by or result in pathological alterations of the complex relationship between the TGF-b family of signaling mediators and the extracellular matrix in connective tissues.T he transforming growth factor b (TGF-b) family of cytokines comprises the three TGF-b proteins (TGF-b1, TGF-b2, and TGFb3) and related growth and differentiation factors such as activins, inhibins, bone morphogenic proteins (BMPs), and growth and differentiation factors (GDFs). These molecules play critical roles both in normal development and in several pathological conditions, including inflammation, fibrosis, and cancer (reviewed in Li and Flavell 2006;Gordon and Blobe 2008;Ikushima and Miyazono 2010). This review focuses on the role of these proteins in development and homeostasis of the skeleton and other connective tissues (summarized in Fig. 1) and on the diseases that ensue when these pathways are altered. Aberrant signaling in these pathways has been associated with common connective 6 These authors contributed equally to this work.

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“…Alk2 ϩ/fl mice on a mixed C57BL/6; SV129 background or Alk3 ϩ/fl mice on a C57BL/6 background 22,23 were bred to B6.Cg-Tg (Alb-Cre)21Mgn /J mice (The Jackson Laboratory) to generate compound heterozygous animals that were intercrossed to obtain second-generation ( The online version of this article contains a data supplement.…”

Section: Animalsmentioning

confidence: 99%

Perturbation of hepcidin expression by BMP type I receptor deletion induces iron overload in mice

Steinbicker

Bartnikas

Lohmeyer

et al. 2011

Blood

160

170

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Bone morphogenetic protein (BMP) signaling induces hepatic expression of the peptide hormone hepcidin. Hepcidin reduces serum iron levels by promoting degradation of the iron exporter ferroportin. A relative deficiency of hepcidin underlies the pathophysiology of many of the genetically distinct iron overload disorders, collectively termed hereditary hemochromatosis. Conversely, chronic inflammatory conditions and neoplastic diseases can induce high hepcidin levels, leading to impaired mobilization of iron stores and the anemia of chronic disease. Two BMP type I receptors, Alk2 (Acvr1) and Alk3 (Bmpr1a), are expressed in murine hepatocytes. We report that liver-specific deletion of either Alk2 or Alk3 causes iron overload in mice. The iron overload phenotype was more marked in Alk3-than in Alk2-deficient mice, and Alk3 deficiency was associated with a nearly complete ablation of basal BMP signaling and hepci- IntroductionThe hepatic hormone hepcidin regulates serum iron levels in mice and humans by inducing degradation of the iron exporter, ferroportin. 1,2 Low ferroportin levels reduce intestinal iron absorption and the release of iron from macrophage stores. Human hereditary hemochromatosis is characterized by low hepcidin levels, leading to iron accumulation in liver, heart, and endocrine organs. 1,3 Similarly, hepcidin deficiency causes hepatic iron overload in mice. 2,4 In contrast, high hepcidin levels contribute to the anemia of chronic disease (ACD) by reducing iron bioavailability for erythropoiesis. 5,6 Recent studies have demonstrated a critical role for bone morphogenetic protein (BMP) signaling in the regulation of hepcidin expression by iron. [7][8][9][10][11] Binding of BMP ligands to type I and type II BMP receptors induces the type II receptor to phosphorylate and activate the type I receptor. The activated type I receptor, in turn, phosphorylates intracellular signaling molecules, including SMADs 1, 5, and 8. Phosphorylated SMADs 1, 5, and 8 bind SMAD4 and together translocate to the nucleus, where they activate the expression of genes, including hepcidin and the Id family of transcription factors. 12 Deficiency of Smad4, 10 the BMP coreceptor hemojuvelin, 13,14 or BMP6 15,16 in hepatocytes reduces expression of hepcidin 17,18 and induces iron overload. In addition, BMP signaling appears to have an important role in the induction of hepcidin expression by inflammatory mediators that are involved in ACD. 11,19,20 There are 4 type I BMP receptors: Alk1, Alk2, Alk3, and Alk6. The identity of the type I BMP receptor(s) responsible for iron-dependent signaling and the regulation of hepcidin expression in hepatocytes are unknown. Alk1 is predominantly expressed in the endothelium. Alk6 is expressed at low levels in murine liver, 21 and global Alk6 deficiency does not induce iron overload in mice (D. R. Campagna, P. J. Schmidt, and M.D.F., unpublished observations, January 2011). In contrast, Alk2 and Alk3 are abundantly expressed in hepatocytes. 21 To identify the type I BMP receptor required for th...

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Craniofacial defects in mice lacking BMP type I receptor Alk2 in neural crest cells

Cited by 195 publications

References 30 publications

Reduction in diabetes‐induced craniofacial defects by maternal immune stimulation

Reduction in diabetes‐induced craniofacial defects by maternal immune stimulation

TGF-β Family Signaling in Connective Tissue and Skeletal Diseases

Perturbation of hepcidin expression by BMP type I receptor deletion induces iron overload in mice

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