Gene Symbol: Spry4
Description: sprouty RTK signaling antagonist 4
Alias: A030006O18Rik, sprouty4, protein sprouty homolog 4, sprouty homolog 4, spry-4
Species: mouse
Products:     Spry4

Top Publications

  1. Taniguchi K, Ayada T, Ichiyama K, Kohno R, Yonemitsu Y, Minami Y, et al. Sprouty2 and Sprouty4 are essential for embryonic morphogenesis and regulation of FGF signaling. Biochem Biophys Res Commun. 2007;352:896-902 pubmed
    ..and Sprouty2 has been investigated using gene targeting approaches, however to date detailed examination of Sprouty4 knockout (KO) mice has not been reported. In this study, Sprouty4 KO mice were generated and characterized...
  2. Klein O, Lyons D, Balooch G, Marshall G, Basson M, Peterka M, et al. An FGF signaling loop sustains the generation of differentiated progeny from stem cells in mouse incisors. Development. 2008;135:377-85 pubmed
    ..Interestingly, although inactivation of Spry4 alone initiates ectopic ameloblast formation in the embryo, the dosage of another sprouty gene must also be ..
  3. Taniguchi K, Sasaki K, Watari K, Yasukawa H, Imaizumi T, Ayada T, et al. Suppression of Sproutys has a therapeutic effect for a mouse model of ischemia by enhancing angiogenesis. PLoS ONE. 2009;4:e5467 pubmed publisher
    ..Sprouty2 and Sprouty4 double knockout (KO) (DKO) mice were embryonic-lethal around E12.5 due to cardiovascular defects...
  4. Charles C, Hovorakova M, Ahn Y, Lyons D, Marangoni P, Churava S, et al. Regulation of tooth number by fine-tuning levels of receptor-tyrosine kinase signaling. Development. 2011;138:4063-73 pubmed publisher
  5. Verheyden J, Sun X. An Fgf/Gremlin inhibitory feedback loop triggers termination of limb bud outgrowth. Nature. 2008;454:638-41 pubmed publisher
    ..Our study unveils the concept of a self-promoting and self-terminating circuit that may be used to attain proper tissue size in a broad spectrum of developmental and regenerative settings. ..
  6. Niwa Y, Masamizu Y, Liu T, Nakayama R, Deng C, Kageyama R. The initiation and propagation of Hes7 oscillation are cooperatively regulated by Fgf and notch signaling in the somite segmentation clock. Dev Cell. 2007;13:298-304 pubmed
    ..We thus propose that Hes7 oscillation is initiated by Fgf signaling and propagated/maintained anteriorly by Notch signaling. ..
  7. Minowada G, Jarvis L, Chi C, Neubüser A, Sun X, Hacohen N, et al. Vertebrate Sprouty genes are induced by FGF signaling and can cause chondrodysplasia when overexpressed. Development. 1999;126:4465-75 pubmed
  8. Zhang S, Lin Y, Itäranta P, Yagi A, Vainio S. Expression of Sprouty genes 1, 2 and 4 during mouse organogenesis. Mech Dev. 2001;109:367-70 pubmed
    ..nasal organs, the follicle of vibrissae and teeth, Sprouty1 and Sprouty2 are expressed in the epithelium and Sprouty4 in the mesenchyme or neuronal tissue, while in the lung Sprouties1, 2 and 4 are all expressed mainly in the ..
  9. Caton J, Luder H, Zoupa M, Bradman M, Bluteau G, Tucker A, et al. Enamel-free teeth: Tbx1 deletion affects amelogenesis in rodent incisors. Dev Biol. 2009;328:493-505 pubmed publisher
    ..These results demonstrate that Tbx1 is essential for the maintenance of ameloblast progenitor cells in rodent incisors and that its deletion results in the absence of enamel formation...

More Information


  1. Klein O, Minowada G, Peterkova R, Kangas A, Yu B, Lesot H, et al. Sprouty genes control diastema tooth development via bidirectional antagonism of epithelial-mesenchymal FGF signaling. Dev Cell. 2006;11:181-90 pubmed
    ..We show that different Sprouty genes are deployed in different tissue compartments--Spry2 in epithelium and Spry4 in mesenchyme--to prevent diastema tooth formation...
  2. 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. ..
  3. de Maximy A, Nakatake Y, Moncada S, Itoh N, Thiery J, Bellusci S. Cloning and expression pattern of a mouse homologue of drosophila sprouty in the mouse embryo. Mech Dev. 1999;81:213-6 pubmed
    ..We have identified three potential mouse homologues of sprouty. One of them, called Sprouty4, exhibits a very restricted expression pattern. At 8...
  4. Impagnatiello M, Weitzer S, Gannon G, Compagni A, Cotten M, Christofori G. Mammalian sprouty-1 and -2 are membrane-anchored phosphoprotein inhibitors of growth factor signaling in endothelial cells. J Cell Biol. 2001;152:1087-98 pubmed
    ..The data indicate that mammalian Spry-1 and -2 are membrane-anchored proteins that negatively regulate angiogenesis-associated RTK signaling, possibly in a RTK-specific fashion. ..
  5. De Langhe S, Carraro G, Warburton D, Hajihosseini M, Bellusci S. Levels of mesenchymal FGFR2 signaling modulate smooth muscle progenitor cell commitment in the lung. Dev Biol. 2006;299:52-62 pubmed
    ..Our work unravels part of the complex interactions that govern normal lung development and may be pertinent to understanding the basis of respiratory defects in Apert syndrome. ..
  6. 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. ..
  7. Nadeau R, Toher J, Yang X, Kovalenko D, Friesel R. Regulation of Sprouty2 stability by mammalian Seven-in-Absentia homolog 2. J Cell Biochem. 2007;100:151-60 pubmed
    ..Co-expression of SIAH2 resulted in proteasomal degradation of Spry1, 2, and to a lesser extent Spry4. The related E3 ubiquitin-ligase, SIAH1, had little effect on Spry2 protein stability when co-expressed...
  8. Ozaki K, Miyazaki S, Tanimura S, Kohno M. Efficient suppression of FGF-2-induced ERK activation by the cooperative interaction among mammalian Sprouty isoforms. J Cell Sci. 2005;118:5861-71 pubmed
    ..Sprouty1 specifically interacts with Grb2, whereas Sprouty4 interacts with Sos1...
  9. Sparrow D, Chapman G, Smith A, Mattar M, Major J, O Reilly V, et al. A mechanism for gene-environment interaction in the etiology of congenital scoliosis. Cell. 2012;149:295-306 pubmed publisher
    ..Our results potentially provide a mechanism for the genesis of a host of common sporadic congenital abnormalities through gene-environment interaction...
  10. Lagronova Churava S, Spoutil F, Vojtechova S, Lesot H, Peterka M, Klein O, et al. The dynamics of supernumerary tooth development are differentially regulated by Sprouty genes. J Exp Zool B Mol Dev Evol. 2013;320:307-20 pubmed publisher
    ..A supernumerary tooth occurs in the diastema of adult mice carrying mutations in either Spry2 or Spry4. In the case of Spry2 mutants, the origin of the supernumerary tooth involves the revitalization of a rudimentary ..
  11. Aberg T, Wang X, Kim J, Yamashiro T, Bei M, Rice R, et al. Runx2 mediates FGF signaling from epithelium to mesenchyme during tooth morphogenesis. Dev Biol. 2004;270:76-93 pubmed
    ..We conclude that Runx2 mediates the functions of epithelial FGF signals regulating Fgf3 expression in the dental mesenchyme and that Fgf3 may be a direct target gene of Runx2. ..
  12. Balasooriya G, Johnson J, Basson M, Rawlins E. An FGFR1-SPRY2 Signaling Axis Limits Basal Cell Proliferation in the Steady-State Airway Epithelium. Dev Cell. 2016;37:85-97 pubmed publisher
    ..We now demonstrate an in vivo biological function of this interaction and thus identify an active signaling mechanism that maintains quiescence in the airway epithelium. ..
  13. Zhang H, Kamiya N, Tsuji T, Takeda H, Scott G, Rajderkar S, et al. Elevated Fibroblast Growth Factor Signaling Is Critical for the Pathogenesis of the Dwarfism in Evc2/Limbin Mutant Mice. PLoS Genet. 2016;12:e1006510 pubmed publisher
    ..Taken together, our data uncover a novel pathogenic mechanism to understand limb dwarfism in patients with Ellis-van Creveld syndrome. ..
  14. Akbulut S, Reddi A, Aggarwal P, Ambardekar C, Canciani B, Kim M, et al. Sprouty proteins inhibit receptor-mediated activation of phosphatidylinositol-specific phospholipase C. Mol Biol Cell. 2010;21:3487-96 pubmed publisher
    ..These data highlight an important action of Spry, which may allow these proteins to influence signaling through multiple receptors. ..
  15. Butterfield N, Metzis V, McGlinn E, Bruce S, Wainwright B, Wicking C. Patched 1 is a crucial determinant of asymmetry and digit number in the vertebrate limb. Development. 2009;136:3515-24 pubmed publisher
    ..These results establish the importance of the downstream consequences of Hh pathway repression, and identify Ptc1 as a key player in limb patterning even prior to the onset of Shh expression. ..
  16. Trokovic N, Trokovic R, Partanen J. Fibroblast growth factor signalling and regional specification of the pharyngeal ectoderm. Int J Dev Biol. 2005;49:797-805 pubmed
    ..Our results suggest that Fgfr1 is important for localized signalling in the pharyngeal ectoderm and consequently for normal tissue interactions in the developing second branchial arch...
  17. Waters S, Lewandoski M. A threshold requirement for Gbx2 levels in hindbrain development. Development. 2006;133:1991-2000 pubmed
    ..markers, this region displays robust expression of Fgf8 and Fgf17, as well as the downstream FGF targets Spry1 and Spry4. Additionally, we demonstrate that the cell division regulator cyclin D2 is downregulated, and that cellular ..
  18. Shaw A, Meissner A, Dowdle J, Crowley D, Magendantz M, Ouyang C, et al. Sprouty-2 regulates oncogenic K-ras in lung development and tumorigenesis. Genes Dev. 2007;21:694-707 pubmed
    ..These findings indicate that in the lung, Sprouty-2 plays a critical role in the regulation of oncogenic K-ras, and implicate counter-regulatory mechanisms in the pathogenesis of Ras-based disease. ..
  19. Hayashi S, Shimoda T, Nakajima M, Tsukada Y, Sakumura Y, Dale J, et al. Sprouty4, an FGF inhibitor, displays cyclic gene expression under the control of the notch segmentation clock in the mouse PSM. PLoS ONE. 2009;4:e5603 pubmed publisher
    ..Here, we show that the expression of Sprouty4, which encodes an FGF inhibitor, oscillates in 2-h cycles in the mouse PSM in synchrony with other oscillating ..
  20. Joo A, Long R, Cheng Z, Alexander C, Chang W, Klein O. Sprouty2 regulates endochondral bone formation by modulation of RTK and BMP signaling. Bone. 2016;88:170-179 pubmed publisher
    ..These results identify Spry2 as a critical regulator of endochondral bone formation that modulates signaling in both osteoblast and chondrocyte lineages. ..
  21. Chan K, Wong H, Jin G, Liu B, Cao R, Cao Y, et al. MT1-MMP inactivates ADAM9 to regulate FGFR2 signaling and calvarial osteogenesis. Dev Cell. 2012;22:1176-90 pubmed publisher
    ..These data reveal a regulatory paradigm for FGRF2 signaling and identify MT1-MMP as a critical negative modulator of ADAM9 activity to maintain FGFR2 signaling in calvarial osteogenesis. ..
  22. Wang B, Sinha T, Jiao K, Serra R, Wang J. Disruption of PCP signaling causes limb morphogenesis and skeletal defects and may underlie Robinow syndrome and brachydactyly type B. Hum Mol Genet. 2011;20:271-85 pubmed publisher
    ..These findings provide novel insight into the signaling mechanisms of Wnt5a/Ror2 and the pathogenesis in BDB1 and RRS...
  23. Probst S, Kraemer C, Demougin P, Sheth R, Martin G, Shiratori H, et al. SHH propagates distal limb bud development by enhancing CYP26B1-mediated retinoic acid clearance via AER-FGF signalling. Development. 2011;138:1913-23 pubmed publisher
    ..In summary, SHH promotes distal progression of limb development by enhancing CYP26B1-mediated RA clearance as part of a signalling network linking the SHH/GREM1/AER-FGF feedback loop to the newly identified AER-FGF/CYP26B1/RA module. ..
  24. Zhao Z, Chen C, Rillahan C, Shen R, Kitzing T, McNerney M, et al. Cooperative loss of RAS feedback regulation drives myeloid leukemogenesis. Nat Genet. 2015;47:539-43 pubmed publisher
    ..cells harboring a Kras(G12D) allele retained low levels of Ras signaling owing to negative feedback involving Spry4 that prevented transformation...
  25. Taniguchi K, Ishizaki T, Ayada T, Sugiyama Y, Wakabayashi Y, Sekiya T, et al. Sprouty4 deficiency potentiates Ras-independent angiogenic signals and tumor growth. Cancer Sci. 2009;100:1648-54 pubmed publisher
    ..In this study, we examined the physiological function of Sprouty4 as an angiogenic regulator, using Sprouty4 knockout (KO) mice and cells...
  26. Murcia C, Gulden F, Cherosky N, Herrup K. A genetic study of the suppressors of the Engrailed-1 cerebellar phenotype. Brain Res. 2007;1140:170-8 pubmed
    ..These findings highlight the complexity and plasticity of gene networks involved in brain development. ..
  27. Shimokawa K, Kimura Yoshida C, Nagai N, Mukai K, Matsubara K, Watanabe H, et al. Cell surface heparan sulfate chains regulate local reception of FGF signaling in the mouse embryo. Dev Cell. 2011;21:257-72 pubmed publisher
    ..Together, the results show that spatiotemporal expression of cell surface-tethered HS chains regulate the local reception of FGF-signaling activity during mammalian embryogenesis. ..
  28. Yu T, Yaguchi Y, Echevarria D, Martinez S, Basson M. Sprouty genes prevent excessive FGF signalling in multiple cell types throughout development of the cerebellum. Development. 2011;138:2957-68 pubmed publisher
    ..Here, we investigated the function of sprouty genes (Spry1, Spry2 and Spry4), which encode feedback antagonists of FGF signalling, during cerebellar development in the mouse...
  29. Sharma B, Joshi S, Sassano A, Majchrzak B, Kaur S, Aggarwal P, et al. Sprouty proteins are negative regulators of interferon (IFN) signaling and IFN-inducible biological responses. J Biol Chem. 2012;287:42352-60 pubmed publisher
    ..In other studies, we found that siRNA-mediated knockdown of Spry1, Spry2, or Spry4 promotes IFN-inducible antileukemic effects in vitro and results in enhanced suppressive effects on malignant ..
  30. Perl A, Hokuto I, Impagnatiello M, Christofori G, Whitsett J. Temporal effects of Sprouty on lung morphogenesis. Dev Biol. 2003;258:154-68 pubmed
    ..These findings demonstrate that the embryonic-pseudoglandular stage is a critical time period during which Spry-sensitive pathways are required for branching morphogenesis, lobulation, and formation of the peripheral lung parenchyma. ..
  31. Hausott B, Vallant N, Schlick B, Auer M, Nimmervoll B, Obermair G, et al. Sprouty2 and -4 regulate axon outgrowth by hippocampal neurons. Hippocampus. 2012;22:434-41 pubmed publisher
    ..In vivo expression of Sprouty2 was reduced by 79% and of Sprouty4 by 93% on postnatal day 14 compared to embryonic day 16.5...
  32. Sylvestersen K, Herrera P, Serup P, Rescan C. Fgf9 signalling stimulates Spred and Sprouty expression in embryonic mouse pancreas mesenchyme. Gene Expr Patterns. 2011;11:105-11 pubmed publisher
  33. Goldman D, Martin G, Tam P. Fate and function of the ventral ectodermal ridge during mouse tail development. Development. 2000;127:2113-23 pubmed
  34. Prochazka J, Prochazkova M, Du W, Spoutil F, Tureckova J, Hoch R, et al. Migration of Founder Epithelial Cells Drives Proper Molar Tooth Positioning and Morphogenesis. Dev Cell. 2015;35:713-24 pubmed publisher
    ..These results demonstrate the importance of intraepithelial cell migration in proper positioning of an initiating organ. ..
  35. Thys A, Vandenberghe P, Hague P, Klein O, Erneux C, Vanderwinden J. Hyperplasia of interstitial cells of cajal in sprouty homolog 4 deficient mice. PLoS ONE. 2015;10:e0124861 pubmed publisher
    ..b>Sprouty homolog 4, a known negative regulator of ERK pathway, has been identified in the interstitial cells of Cajal in the ..
  36. Lochovska K, Peterkova R, Pavlikova Z, Hovorakova M. Sprouty gene dosage influences temporal-spatial dynamics of primary enamel knot formation. BMC Dev Biol. 2015;15:21 pubmed publisher
    ..Using mouse embryos with different dosages of Spry2 and Spry4 genes, we showed that during the normal development of M1 in the mandible the sooner appearing Shh signaling ..
  37. Lin W, Jing N, Basson M, Dierich A, Licht J, Ang S. Synergistic activity of Sef and Sprouty proteins in regulating the expression of Gbx2 in the mid-hindbrain region. Genesis. 2005;41:110-5 pubmed
    ..Altogether, our results demonstrate that Sef and Sproutys function synergistically to regulate Gbx2 expression in the anterior hindbrain. ..
  38. Patel N, Sharpe P, Miletich I. Coordination of epithelial branching and salivary gland lumen formation by Wnt and FGF signals. Dev Biol. 2011;358:156-67 pubmed publisher
    ..Altogether, these findings point to a key function of FGF signaling in the maintenance of an undifferentiated state in endbud cells by inhibition of a ductal fate...
  39. Thongrong S, Hausott B, Marvaldi L, Agostinho A, Zangrandi L, Burtscher J, et al. Sprouty2 and -4 hypomorphism promotes neuronal survival and astrocytosis in a mouse model of kainic acid induced neuronal damage. Hippocampus. 2016;26:658-67 pubmed publisher
    ..Among the four Sprouty isoforms, Spry2 and Spry4 are expressed in the hippocampus...
  40. Warrier S, Nuwayhid S, Sabatino J, Sugrue K, Zohn I. Supt20 is required for development of the axial skeleton. Dev Biol. 2017;421:245-257 pubmed publisher
    ..We demonstrate that Gcn5 and Supt20 hypomorphs show similar defects in rostral-caudal somite patterning potentially suggesting shared mechanisms. ..
  41. Farin H, Lüdtke T, Schmidt M, Placzko S, Schuster Gossler K, Petry M, et al. Tbx2 terminates shh/fgf signaling in the developing mouse limb bud by direct repression of gremlin1. PLoS Genet. 2013;9:e1003467 pubmed publisher
    ..We propose that proliferative expansion of Tbx2-expressing cells mediates self-termination of limb bud outgrowth due to their refractoriness to Grem1 induction. ..
  42. Miraoui H, Dwyer A, Sykiotis G, Plummer L, CHUNG W, Feng B, et al. Mutations in FGF17, IL17RD, DUSP6, SPRY4, and FLRT3 are identified in individuals with congenital hypogonadotropic hypogonadism. Am J Hum Genet. 2013;92:725-43 pubmed publisher
    ..other genes were found to be mutated in CHH individuals: FGF17 (n = 3 individuals), IL17RD (n = 8), DUSP6 (n = 5), SPRY4 (n = 14), and FLRT3 (n = 3)...
  43. Li C, Cha W, Luder H, Charles R, McMahon M, Mitsiadis T, et al. E-cadherin regulates the behavior and fate of epithelial stem cells and their progeny in the mouse incisor. Dev Biol. 2012;366:357-66 pubmed publisher
    ..Together, our data indicate that E-cadherin is an important regulator of stem cells and their progeny during growth of the mouse incisor. ..
  44. van Rooijen C, Simmini S, Bialecka M, Neijts R, van de Ven C, Beck F, et al. Evolutionarily conserved requirement of Cdx for post-occipital tissue emergence. Development. 2012;139:2576-83 pubmed publisher
    ..Cdx requirement for the post-head section of the axis is ancestral as it takes place in arthropods as well. ..
  45. Gromova P, Ralea S, Lefort A, Libert F, Rubin B, Erneux C, et al. Kit K641E oncogene up-regulates Sprouty homolog 4 and trophoblast glycoprotein in interstitial cells of Cajal in a murine model of gastrointestinal stromal tumours. J Cell Mol Med. 2009;13:1536-48 pubmed publisher
    ..Gja1/Cx43, Gpc6, Gpr133, Pacrg, Pde3a, Prkar2b, Prkcq/Pkce, Rasd2, Spry4 and Tpbg/5T4 were found to be up-regulated...
  46. Goldshmit Y, Frisca F, Kaslin J, Pinto A, Tang J, Pébay A, et al. Decreased anti-regenerative effects after spinal cord injury in spry4-/- mice. Neuroscience. 2015;287:104-12 pubmed publisher
    ..2012, 2014). One of the downstream signaling target genes of Fgf is spry4, which acts as a feedback inhibitor for Fgf signaling...
  47. Gong Y, Yang X, He Q, Gower L, Prudovsky I, Vary C, et al. Sprouty4 regulates endothelial cell migration via modulating integrin ?3 stability through c-Src. Angiogenesis. 2013;16:861-75 pubmed publisher
    ..The RTK modulator, Sprouty4 (Spry4) inhibits endothelial cell functions and angiogenesis, but the mechanisms remain to be fully elucidated...
  48. Yang X, Harkins L, Zubanova O, Harrington A, Kovalenko D, Nadeau R, et al. Overexpression of Spry1 in chondrocytes causes attenuated FGFR ubiquitination and sustained ERK activation resulting in chondrodysplasia. Dev Biol. 2008;321:64-76 pubmed publisher
  49. Naiche L, Holder N, Lewandoski M. FGF4 and FGF8 comprise the wavefront activity that controls somitogenesis. Proc Natl Acad Sci U S A. 2011;108:4018-23 pubmed publisher
    ..Furthermore, these data show that FGF action maintains WNT signaling, and that both signaling pathways are required in parallel to maintain PSM progenitor tissue. ..
  50. Jäggi F, Cabrita M, Perl A, Christofori G. Modulation of endocrine pancreas development but not beta-cell carcinogenesis by Sprouty4. Mol Cancer Res. 2008;6:468-82 pubmed publisher
    ..Here, by the inducible expression of murine Spry4 in pancreatic beta cells, we have assessed the functional role of Spry proteins in the development of pancreatic ..
  51. Kyrylkova K, Kyryachenko S, Biehs B, Klein O, Kioussi C, Leid M. BCL11B regulates epithelial proliferation and asymmetric development of the mouse mandibular incisor. PLoS ONE. 2012;7:e37670 pubmed publisher
    ..Our data integrate BCL11B into these pathways during incisor development and reveal the molecular mechanisms that underlie phenotypes of both Bcl11b(-/-) and Sprouty mutant mice. ..
  52. Petersen C, Jheon A, Mostowfi P, Charles C, Ching S, Thirumangalathu S, et al. FGF signaling regulates the number of posterior taste papillae by controlling progenitor field size. PLoS Genet. 2011;7:e1002098 pubmed publisher
  53. Thomson R, Pellicano F, Iwata T. Fibroblast growth factor receptor 3 kinase domain mutation increases cortical progenitor proliferation via mitogen-activated protein kinase activation. J Neurochem. 2007;100:1565-78 pubmed
    ..We suggest that temporal activation of MAPK is largely responsible for cell proliferation caused by the Fgfr3 mutation during early stages of cortical development. ..