Genomes and Genes
Gene Symbol: Grem1
Description: gremlin 1, DAN family BMP antagonist
Alias: Cktsf1b1, Drm, Grem, gremlin-1, cysteine knot superfamily 1, BMP antagonist 1, down-regulated in Mos-transformed cells protein, down-regulated in v-mos-transformed cells
- Lewandoski M, Sun X, Martin G. Fgf8 signalling from the AER is essential for normal limb development. Nat Genet. 2000;26:460-3 pubmed..Our data identify Fgf8 as the only known AER-Fgf individually necessary for normal limb development, and provide insight into the function of Fgf signalling from the AER in the normal outgrowth and patterning of the limb. ..
- Vokes S, Ji H, Wong W, McMahon A. A genome-scale analysis of the cis-regulatory circuitry underlying sonic hedgehog-mediated patterning of the mammalian limb. Genes Dev. 2008;22:2651-63 pubmed publisher..These studies provide the first comprehensive characterization of the transcriptional output of a Shh-patterning process in the mammalian embryo and a framework for elaborating regulatory networks in the developing limb. ..
- Litingtung Y, Dahn R, Li Y, Fallon J, Chiang C. Shh and Gli3 are dispensable for limb skeleton formation but regulate digit number and identity. Nature. 2002;418:979-83 pubmed
- te Welscher P, Zuniga A, Kuijper S, Drenth T, Goedemans H, Meijlink F, et al. Progression of vertebrate limb development through SHH-mediated counteraction of GLI3. Science. 2002;298:827-30 pubmed..Our genetic analysis indicates that SHH signaling counteracts GLI3-mediated repression of key regulator genes, cell survival, and distal progression of limb bud development. ..
- Khokha M, Hsu D, Brunet L, Dionne M, Harland R. Gremlin is the BMP antagonist required for maintenance of Shh and Fgf signals during limb patterning. Nat Genet. 2003;34:303-7 pubmed..We tested this model directly by mutating the mouse gene encoding gremlin (Cktsf1b1, herein called gremlin)...
- Suzuki T, Takeuchi J, Koshiba Takeuchi K, Ogura T. Tbx Genes Specify Posterior Digit Identity through Shh and BMP Signaling. Dev Cell. 2004;6:43-53 pubmed..Hence, we conclude that Tbx3 specifies digit III, and the combination of Tbx2 and Tbx3 specifies digit IV, acting together with the interdigital BMP signaling cascade. ..
- Hill P, Götz K, Ruther U. A SHH-independent regulation of Gli3 is a significant determinant of anteroposterior patterning of the limb bud. Dev Biol. 2009;328:506-16 pubmed publisher..Furthermore, we present evidence that the anteroposterior grading of GLI3 activity by the action of SHH is supported by a prototype patterning, which regulates Gli3 independently from SHH. ..
- Costello C, Howell K, Cahill E, McBryan J, Konigshoff M, Eickelberg O, et al. Lung-selective gene responses to alveolar hypoxia: potential role for the bone morphogenetic antagonist gremlin in pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol. 2008;295:L272-84 pubmed publisher..From one cluster, we confirmed that the bone morphogenetic protein (BMP) antagonist, gremlin 1, was upregulated in the hypoxic murine lung in vivo but was unchanged in five systemic organs...
- Hsu D, Economides A, Wang X, Eimon P, Harland R. The Xenopus dorsalizing factor Gremlin identifies a novel family of secreted proteins that antagonize BMP activities. Mol Cell. 1998;1:673-83 pubmed..Therefore, we propose that Gremlin, Cerberus, and DAN control diverse processes in growth and development by selectively antagonizing the activities of different subsets of the TGF beta ligands. ..
- Michos O, Gonçalves A, Lopez Rios J, Tiecke E, Naillat F, Beier K, et al. Reduction of BMP4 activity by gremlin 1 enables ureteric bud outgrowth and GDNF/WNT11 feedback signalling during kidney branching morphogenesis. Development. 2007;134:2397-405 pubmed..In mouse embryos lacking the extra-cellular BMP antagonist gremlin 1 (Grem1), metanephric development is disrupted at the stage of initiating ureteric bud outgrowth...
- Bensoussan Trigano V, Lallemand Y, Saint Cloment C, Robert B. Msx1 and Msx2 in limb mesenchyme modulate digit number and identity. Dev Dyn. 2011;240:1190-202 pubmed publisher..With this strategy, we demonstrate that mesenchymal expression of Msx1 and Msx2 is required for proper Shh and Bmp4 signaling to specify digit number and identity...
- Gonçalves A, Zeller R. Genetic analysis reveals an unexpected role of BMP7 in initiation of ureteric bud outgrowth in mouse embryos. PLoS ONE. 2011;6:e19370 pubmed publisherGenetic analysis in the mouse revealed that GREMLIN1 (GREM1)-mediated antagonism of BMP4 is essential for ureteric epithelial branching as the disruption of ureteric bud outgrowth and renal agenesis in Grem1-deficient embryos is restored ..
- Verheyden J, Lewandoski M, Deng C, Harfe B, Sun X. Conditional inactivation of Fgfr1 in mouse defines its role in limb bud establishment, outgrowth and digit patterning. Development. 2005;132:4235-45 pubmed..Our study of these two Fgfr1 conditional mutants has elucidated the multiple roles of FGFR1 in limb bud establishment, growth and patterning. ..
- Gazzerro E, Smerdel Ramoya A, Zanotti S, Stadmeyer L, Durant D, Economides A, et al. Conditional deletion of gremlin causes a transient increase in bone formation and bone mass. J Biol Chem. 2007;282:31549-57 pubmed..To define the function of gremlin in the skeleton, we generated gremlin 1 (grem1) conditional null mice by mating mice where grem1 was flanked by lox(P) sequences with mice expressing ..
- Zhou F, Leder P, Zuniga A, Dettenhofer M. Formin1 disruption confers oligodactylism and alters Bmp signaling. Hum Mol Genet. 2009;18:2472-82 pubmed publisher..Additionally, these studies show enhanced activity downstream of the Bmp receptor in cells where Fmn1 is perturbed, suggesting a role for Fmn1 in repression of Bmp signaling...
- Mitola S, Ravelli C, Moroni E, Salvi V, Leali D, Ballmer Hofer K, et al. Gremlin is a novel agonist of the major proangiogenic receptor VEGFR2. Blood. 2010;116:3677-80 pubmed publisher..Gremlin thus represents a novel proangiogenic VEGFR2 agonist distinct from the VEGF family ligands with implications in vascular development, angiogenesis-dependent diseases, and tumor neovascularization. ..
- Zhang Q, Shi Y, Wada J, Malakauskas S, Liu M, Ren Y, et al. In vivo delivery of Gremlin siRNA plasmid reveals therapeutic potential against diabetic nephropathy by recovering bone morphogenetic protein-7. PLoS ONE. 2010;5:e11709 pubmed publisher..We conclude that inhibition of Gremlin exerts beneficial effects on the diabetic kidney mainly through maintenance of BMP-7 activity and that Gremlin may serve as a novel therapeutic target in the management of diabetic nephropathy. ..
- Self M, Geng X, Oliver G. Six2 activity is required for the formation of the mammalian pyloric sphincter. Dev Biol. 2009;334:409-17 pubmed publisher..5, Sox9, and Gremlin) also appear to be required for the formation of this structure in mammals. Thus, we propose that Six2 activity regulates this gene network during the genesis of the pyloric sphincter in the mouse...
- Charite J, McFadden D, Olson E. The bHLH transcription factor dHAND controls Sonic hedgehog expression and establishment of the zone of polarizing activity during limb development. Development. 2000;127:2461-70 pubmed..Together, these findings identify dHAND as an upstream activator of Shh expression and important transcriptional regulator of limb development. ..
- Lu P, Yu Y, Perdue Y, Werb Z. The apical ectodermal ridge is a timer for generating distal limb progenitors. Development. 2008;135:1395-405 pubmed publisher..Taken together, we have uncovered a novel mechanism, whereby the AER regulates the number of autopod progenitors by determining the onset of their generation. ..
- Liu N, Barbosa A, Chapman S, Bezprozvannaya S, Qi X, Richardson J, et al. DNA binding-dependent and -independent functions of the Hand2 transcription factor during mouse embryogenesis. Development. 2009;136:933-42 pubmed publisher..These findings suggest that Hand2 regulates tissue growth and development in vivo through DNA binding-dependent and -independent mechanisms. ..
- Zuniga A, Quillet R, Perrin Schmitt F, Zeller R. Mouse Twist is required for fibroblast growth factor-mediated epithelial-mesenchymal signalling and cell survival during limb morphogenesis. Mech Dev. 2002;114:51-9 pubmed..Finally, Twist function, most likely by regulating FGF signalling, is required for cell survival as apoptotic cells are detected in posterior and distal limb bud mesenchyme. ..
- Barna M, Pandolfi P, Niswander L. Gli3 and Plzf cooperate in proximal limb patterning at early stages of limb development. Nature. 2005;436:277-81 pubmed..The initial division of the vertebrate limb into two distinct molecular domains is consistent with fossil evidence indicating that the upper and lower extremities of the limb have different evolutionary origins. ..
- Scherz P, Harfe B, McMahon A, Tabin C. The limb bud Shh-Fgf feedback loop is terminated by expansion of former ZPA cells. Science. 2004;305:396-9 pubmed
- Roxburgh S, Kattla J, Curran S, O Meara Y, Pollock C, Goldschmeding R, et al. Allelic depletion of grem1 attenuates diabetic kidney disease. Diabetes. 2009;58:1641-50 pubmed publisherGremlin (grem1) is an antagonist of the bone morphogenetic protein family that plays a key role in limb bud development and kidney formation...
- Galli A, Robay D, Osterwalder M, Bao X, Bénazet J, Tariq M, et al. Distinct roles of Hand2 in initiating polarity and posterior Shh expression during the onset of mouse limb bud development. PLoS Genet. 2010;6:e1000901 pubmed publisher..Our study uncovers essential components of the transcriptional machinery and key interactions that set-up limb bud asymmetry upstream of establishing the SHH signaling limb bud organizer. ..
- Sheth R, Bastida M, Ros M. Hoxd and Gli3 interactions modulate digit number in the amniote limb. Dev Biol. 2007;310:430-41 pubmed..Our results also support the notion that an adequate balance between positive and negative effects of different Hoxd genes is required for pentadactyly. ..
- Lallemand Y, Nicola M, Ramos C, Bach A, Cloment C, Robert B. Analysis of Msx1; Msx2 double mutants reveals multiple roles for Msx genes in limb development. Development. 2005;132:3003-14 pubmed..This results in a major outgrowth of the mesenchyme anteriorly, which nevertheless maintains a posterior identity, and leads to formation of extra digits. These defects are interpreted in the context of an impairment of Bmp signalling. ..
- Li X, Udager A, Hu C, Qiao X, Richards N, Gumucio D. Dynamic patterning at the pylorus: formation of an epithelial intestine-stomach boundary in late fetal life. Dev Dyn. 2009;238:3205-17 pubmed publisher..Finally, we define a unique expression domain at the pylorus itself and detect novel pylorus-specific patterns for the transcription factor Gata3 and the secreted protein nephrocan...
- Zuniga A, Haramis A, McMahon A, Zeller R. Signal relay by BMP antagonism controls the SHH/FGF4 feedback loop in vertebrate limb buds. Nature. 1999;401:598-602 pubmed
- Walsh D, Roxburgh S, McGettigan P, Berthier C, Higgins D, Kretzler M, et al. Co-regulation of Gremlin and Notch signalling in diabetic nephropathy. Biochim Biophys Acta. 2008;1782:10-21 pubmed..Together, these data suggest that Notch pathway gene expression is elevated in diabetic nephropathy, co-incident with Gremlin, and may contribute to the pathogenesis of this disease. ..
- Zuniga A, Michos O, Spitz F, Haramis A, Panman L, Galli A, et al. Mouse limb deformity mutations disrupt a global control region within the large regulatory landscape required for Gremlin expression. Genes Dev. 2004;18:1553-64 pubmed..Our studies reveal the large genomic landscape harboring this GCR, which is required for tissue-specific coexpression of two structurally and functionally unrelated genes. ..
- Pearce J, Penny G, Rossant J. A mouse cerberus/Dan-related gene family. Dev Biol. 1999;209:98-110 pubmed..In the mouse, there are at least five family members: Cer1, Drm, PRDC, Dan, and Dte...
- Shi W, Zhao J, Anderson K, Warburton D. Gremlin negatively modulates BMP-4 induction of embryonic mouse lung branching morphogenesis. Am J Physiol Lung Cell Mol Physiol. 2001;280:L1030-9 pubmed..Therefore, our data support the hypothesis that Gremlin is a physiologically negative regulator of BMP-4 in lung branching morphogenesis...
- Stabile H, Mitola S, Moroni E, Belleri M, Nicoli S, Coltrini D, et al. Bone morphogenic protein antagonist Drm/gremlin is a novel proangiogenic factor. Blood. 2007;109:1834-40 pubmedAngiogenesis plays a key role in various physiologic and pathologic conditions, including tumor growth. Drm/gremlin, a member the Dan family of bone morphogenic protein (BMP) antagonists, is commonly thought to affect different processes ..
- Weatherbee S, Niswander L, Anderson K. A mouse model for Meckel syndrome reveals Mks1 is required for ciliogenesis and Hedgehog signaling. Hum Mol Genet. 2009;18:4565-75 pubmed publisher..Thus the disruption of Hh signaling can explain many, but not all, of the defects caused by loss of Mks1...
- Michos O, Panman L, Vintersten K, Beier K, Zeller R, Zuniga A. Gremlin-mediated BMP antagonism induces the epithelial-mesenchymal feedback signaling controlling metanephric kidney and limb organogenesis. Development. 2004;131:3401-10 pubmed..This study establishes that the BMP antagonist gremlin (Grem1) is essential to initiate these epithelial-mesenchymal signaling interactions during limb and metanephric kidney ..
- Panman L, Galli A, Lagarde N, Michos O, Soete G, Zuniga A, et al. Differential regulation of gene expression in the digit forming area of the mouse limb bud by SHH and gremlin 1/FGF-mediated epithelial-mesenchymal signalling. Development. 2006;133:3419-28 pubmed..manipulation of signalling to analyze the kinetics by which the SHH morphogen and the BMP antagonist gremlin 1 (GREM1) control gene expression in the digit-forming mesenchyme of mouse limb buds...
- Sun X, Mariani F, Martin G. Functions of FGF signalling from the apical ectodermal ridge in limb development. Nature. 2002;418:501-8 pubmed..In the complete absence of both FGF4 and FGF8 activities, limb development fails. We present a model to explain how the mutant phenotypes arise from FGF-mediated effects on limb bud size and cell survival. ..
- Kuhlman J, Niswander L. Limb deformity proteins: role in mesodermal induction of the apical ectodermal ridge. Development. 1997;124:133-9 pubmed..Ld proteins appear to act during the differentiation phase. ..
- McDowell C, Hernandez H, Mao W, Clark A. Gremlin Induces Ocular Hypertension in Mice Through Smad3-Dependent Signaling. Invest Ophthalmol Vis Sci. 2015;56:5485-92 pubmed publisher..These data show that gremlin signals through the Smad3-dependent pathway in the TM to elevate IOP. We determined for the first time gremlin's role in inducing ocular hypertension in an in vivo model system. ..
- Li J, Wang Q, Cui Y, Yang X, Li Y, Zhang X, et al. Suppressor of Fused Is Required for Determining Digit Number and Identity via Gli3/Fgfs/Gremlin. PLoS ONE. 2015;10:e0128006 pubmed publisher..Thus, we provide evidence that Sufu is involved in the genetic network that restricts the posterior expression of Gli2/3/Hand2 and Gremlin/Fgf in limb bud patterning. ..
- Li Q, Lewandowski J, Powell M, Norrie J, Cho S, Vokes S. A Gli silencer is required for robust repression of gremlin in the vertebrate limb bud. Development. 2014;141:1906-14 pubmed publisher..the first genetic characterization of a Gli-dependent cis-regulatory module (CRM), focusing on its regulation of Grem1 in the mouse limb bud. The CRM, termed GRE1 (Gli responsive element 1), can act as both an enhancer and a silencer...
- Lu M, Yang H, Zhang L, Shu W, Blair D, Morrisey E. The bone morphogenic protein antagonist gremlin regulates proximal-distal patterning of the lung. Dev Dyn. 2001;222:667-80 pubmed..These data suggest that gremlin plays an important role in lung morphogenesis by regulating the proximal-distal patterning of the lung during development. ..
- Canalis E, Parker K, Zanotti S. Gremlin1 is required for skeletal development and postnatal skeletal homeostasis. J Cell Physiol. 2012;227:269-77 pubmed publisher..Inactivation of Grem1 results in severe developmental defects, but the consequences of the global inactivation of Grem1 on the postnatal ..
- Treichel D, Schock F, Jackle H, Gruss P, Mansouri A. mBtd is required to maintain signaling during murine limb development. Genes Dev. 2003;17:2630-5 pubmed..The data indicate that mBtd represents a novel key player mediating proximodistal outgrowth of the limb. ..
- Wang C, Ruther U, Wang B. The Shh-independent activator function of the full-length Gli3 protein and its role in vertebrate limb digit patterning. Dev Biol. 2007;305:460-9 pubmed
- Bénazet J, Zeller R. Dual requirement of ectodermal Smad4 during AER formation and termination of feedback signaling in mouse limb buds. Genesis. 2013;51:660-6 pubmed publisher..In summary, our genetic analysis reveals the temporally and functionally distinct dual requirement of ectodermal Smad4 during initiation and termination of AER signaling. ..
- Martinelli D, Fan C. Gas1 extends the range of Hedgehog action by facilitating its signaling. Genes Dev. 2007;21:1231-43 pubmed..Our data support a model in which GAS1 helps transform the Hedgehog protein gradient into the observed activity gradient. We propose that Gas1 is an evolutionarily novel, vertebrate-specific Hedgehog pathway regulator. ..
- Liu Y, Chen Z, Cheng H, Chen J, Qian J. Gremlin promotes retinal pigmentation epithelial (RPE) cell proliferation, migration and VEGF production via activating VEGFR2-Akt-mTORC2 signaling. Oncotarget. 2017;8:979-987 pubmed publisher..We conclude that gremlin promotes RPE cell proliferation, migration and VEGF production possibly via activating VEGFR2-Akt-mTORC2 signaling. Gremlin could be a novel therapeutic target of ROP or other retinal vasoproliferation diseases. ..