Gene Symbol: Six4
Description: sine oculis-related homeobox 4
Alias: AI047561, AREC3, TrexBF, homeobox protein SIX4, sine oculis-related homeobox 4 homolog, skeletal muscle-specific ARE-binding protein AREC3
Species: mouse
Products:     Six4

Top Publications

  1. Spitz F, Demignon J, Porteu A, Kahn A, Concordet J, Daegelen D, et al. Expression of myogenin during embryogenesis is controlled by Six/sine oculis homeoproteins through a conserved MEF3 binding site. Proc Natl Acad Sci U S A. 1998;95:14220-5 pubmed
    ..Antibodies directed specifically against Six1 or Six4 proteins reveal that each of these proteins is present in the embryo when myogenin is activated and constitutes a ..
  2. Ohto H, Takizawa T, Saito T, Kobayashi M, Ikeda K, Kawakami K. Tissue and developmental distribution of Six family gene products. Int J Dev Biol. 1998;42:141-8 pubmed
    ..The distribution of Six2 and Six4 was examined by immunostaining in the developing mouse embryo. Production of Six2 was detected at E8...
  3. Ohto H, Kamada S, Tago K, Tominaga S, Ozaki H, Sato S, et al. Cooperation of six and eya in activation of their target genes through nuclear translocation of Eya. Mol Cell Biol. 1999;19:6815-24 pubmed, myogenin promoter, and on a synthetic promoter, the thymidine kinase gene promoter fused to multimerized Six4 binding sites...
  4. Grifone R, Demignon J, Giordani J, Niro C, Souil E, Bertin F, et al. Eya1 and Eya2 proteins are required for hypaxial somitic myogenesis in the mouse embryo. Dev Biol. 2007;302:602-16 pubmed
    In mammals, Pax3, Six4, Six1 and Six5 genes are co-expressed with Eya1, Eya2 and Eya4 genes during mouse somitogenesis...
  5. Ozaki H, Nakamura K, Funahashi J, Ikeda K, Yamada G, Tokano H, et al. Six1 controls patterning of the mouse otic vesicle. Development. 2004;131:551-62 pubmed
    ..In spite of the similarity of otic phenotypes of Six1- and Shh-deficient mice, expressions of Six1 and Shh were mutually independent. ..
  6. Seenundun S, Rampalli S, Liu Q, Aziz A, Palii C, Hong S, et al. UTX mediates demethylation of H3K27me3 at muscle-specific genes during myogenesis. EMBO J. 2010;29:1401-11 pubmed publisher
    ..Although the transactivator Six4 initially recruits UTX to the regulatory region of muscle genes, the resulting loss of H3K27me3 marks is limited to ..
  7. Niro C, Demignon J, Vincent S, Liu Y, Giordani J, Sgarioto N, et al. Six1 and Six4 gene expression is necessary to activate the fast-type muscle gene program in the mouse primary myotome. Dev Biol. 2010;338:168-82 pubmed publisher
    ..Affymetrix transcriptomal analysis of Six1(-/-)Six4(-/-) E10.5 somites revealed the specific down-regulation of many genes of the fast-type muscle program...
  8. Ikeda K, Watanabe Y, Ohto H, Kawakami K. Molecular interaction and synergistic activation of a promoter by Six, Eya, and Dach proteins mediated through CREB binding protein. Mol Cell Biol. 2002;22:6759-66 pubmed
    ..This work provides fundamental information on the role and the mechanism of action of this gene cassette in tissue differentiation and organogenesis. ..
  9. Laclef C, Hamard G, Demignon J, Souil E, Houbron C, Maire P. Altered myogenesis in Six1-deficient mice. Development. 2003;130:2239-52 pubmed
    ..It appears therefore that Six1 plays a specific role in hypaxial muscle differentiation, distinct from those of other hypaxial determinants such as Pax3, cMet, Lbx1 or Mox2. ..

Scientific Experts

More Information


  1. Grifone R, Demignon J, Houbron C, Souil E, Niro C, Seller M, et al. Six1 and Six4 homeoproteins are required for Pax3 and Mrf expression during myogenesis in the mouse embryo. Development. 2005;132:2235-49 pubmed
    In mammals, Six5, Six4 and Six1 genes are co-expressed during mouse myogenesis. Six4 and Six5 single knockout (KO) mice have no developmental defects, while Six1 KO mice die at birth and show multiple organ developmental defects...
  2. Giordani J, Bajard L, Demignon J, Daubas P, Buckingham M, Maire P. Six proteins regulate the activation of Myf5 expression in embryonic mouse limbs. Proc Natl Acad Sci U S A. 2007;104:11310-5 pubmed
    ..In the present study we show that Myf5 expression is severely impaired in the limb buds of Six1(-/-) and Six1(-/-)Six4(-/+) mouse mutants despite the presence of myogenic progenitor cells...
  3. Konishi Y, Ikeda K, Iwakura Y, Kawakami K. Six1 and Six4 promote survival of sensory neurons during early trigeminal gangliogenesis. Brain Res. 2006;1116:93-102 pubmed
    ..In the present study, we investigated the role of Six1 and Six4 in the development of trigeminal ganglia...
  4. Ando Z, Sato S, Ikeda K, Kawakami K. Slc12a2 is a direct target of two closely related homeobox proteins, Six1 and Six4. FEBS J. 2005;272:3026-41 pubmed
    ..Of the six family members (Six1-Six6) in mice, Six1 and Six4 show similar expression patterns during embryogenesis...
  5. Himeda C, Ranish J, Angello J, Maire P, Aebersold R, Hauschka S. Quantitative proteomic identification of six4 as the trex-binding factor in the muscle creatine kinase enhancer. Mol Cell Biol. 2004;24:2132-43 pubmed
    ..After selectively enriching for the Trex-binding factor (TrexBF) using magnetic beads coupled to oligonucleotides containing either wild-type or mutant Trex sites, quantitative ..
  6. Ozaki H, Watanabe Y, Takahashi K, Kitamura K, Tanaka A, Urase K, et al. Six4, a putative myogenin gene regulator, is not essential for mouse embryonal development. Mol Cell Biol. 2001;21:3343-50 pubmed
    b>Six4 is a member of the Six family genes, homologues of Drosophila melanogaster sine oculis...
  7. Xu J, Xu P. Eya-six are necessary for survival of nephrogenic cord progenitors and inducing nephric duct development before ureteric bud formation. Dev Dyn. 2015;244:866-73 pubmed publisher
    ..The nephrogenic progenitor population is initially present but significantly reduced in mice lacking both Six1 and Six4 and undertakes an abnormal cell death pathway to be completely eliminated by ∼E10.5-E11...
  8. Ozaki H, Yamada K, Kobayashi M, Asakawa S, Minoshima S, Shimizu N, et al. Structure and chromosome mapping of the human SIX4 and murine Six4 genes. Cytogenet Cell Genet. 1999;87:108-12 pubmed
    b>Six4, a member of the homeobox gene subfamily (Six), is expressed in a developmentally regulated fashion, and supposed to be involved in embryogenesis. We cloned the human SIX4 and murine Six4 genomic DNAs and determined their structures...
  9. Daubas P, Buckingham M. Direct molecular regulation of the myogenic determination gene Myf5 by Pax3, with modulation by Six1/4 factors, is exemplified by the -111 kb-Myf5 enhancer. Dev Biol. 2013;376:236-44 pubmed publisher
    ..However, in the case of the -111 kb-Myf5 enhancer, Six has less effect and we conclude that Pax regulation plays a major role in controlling this aspect of the Myf5 gene expression at the onset of myogenesis in the embryo. ..
  10. Yajima H, Kawakami K. Low Six4 and Six5 gene dosage improves dystrophic phenotype and prolongs life span of mdx mice. Dev Growth Differ. 2016;58:546-61 pubmed publisher
    ..We demonstrated previously the involvement of homeobox transcription factors, SIX1, SIX4 and SIX5, in the coordinated proliferation and differentiation of isolated satellite cells in vitro...
  11. Kawakami K, Ohto H, Ikeda K, Roeder R. Structure, function and expression of a murine homeobox protein AREC3, a homologue of Drosophila sine oculis gene product, and implication in development. Nucleic Acids Res. 1996;24:303-10 pubmed
    The cDNA clones encoding ARE(Na,K-ATPase alpha1 subunit gene regulatory element) binding protein AREC3 were isolated from myoblast C2C12 cells and mouse skeletal muscle cDNA library...
  12. Suzuki Y, Ikeda K, Kawakami K. Development of gustatory papillae in the absence of Six1 and Six4. J Anat. 2011;219:710-21 pubmed publisher
    ..We show here that embryos lacking both Six1 and Six4 revealed more severe abnormalities than those lacking Six1 alone during morphogenesis of their gustatory papillae...
  13. Niiya A, Ohto H, Kawakami K, Araki M. Localization of Six4/AREC3 in the developing mouse retina; implications in mammalian retinal development. Exp Eye Res. 1998;67:699-707 pubmed
    The Six4/AREC3 gene was originally isolated as a regulatory factor which bound to the positive regulatory region of the Na, K-ATPase alpha 1 subunit...
  14. Richard A, Demignon J, Sakakibara I, Pujol J, Favier M, Strochlic L, et al. Genesis of muscle fiber-type diversity during mouse embryogenesis relies on Six1 and Six4 gene expression. Dev Biol. 2011;359:303-20 pubmed publisher
    ..Genesis of this fiber-type heterogeneity during development remains poorly known, at least in mammals. Six1 and Six4 homeoproteins of the Six/sine oculis family are expressed throughout muscle development in mice, and Six1 protein ..
  15. Kutejova E, Engist B, Mallo M, Kanzler B, Bobola N. Hoxa2 downregulates Six2 in the neural crest-derived mesenchyme. Development. 2005;132:469-78 pubmed
    ..Furthermore, we demonstrate that Hoxa2 regulation of Six2 is confined to a 0.9 kb fragment of the Six2 promoter and that Hoxa2 binds to this promoter region. These results strongly suggest that Six2 is a direct target of Hoxa2. ..
  16. He G, Tavella S, Hanley K, Self M, Oliver G, Grifone R, et al. Inactivation of Six2 in mouse identifies a novel genetic mechanism controlling development and growth of the cranial base. Dev Biol. 2010;344:720-30 pubmed publisher
    ..The comparable expression during human embryogenesis and the high protein conservation from mouse to human implicate SIX2 loss-of-function as a potential congenital cause of anterior cranial base defects in humans. ..
  17. Nonomura K, Takahashi M, Wakamatsu Y, Takano Yamamoto T, Osumi N. Dynamic expression of Six family genes in the dental mesenchyme and the epithelial ameloblast stem/progenitor cells during murine tooth development. J Anat. 2010;216:80-91 pubmed publisher
    ..We found dynamic expression patterns for Six1, Six2, Six4 and Six5 in the oral epithelium and mesenchymal cells with distinct expression patterns at the early stage before ..
  18. Suzuki Y, Ikeda K, Kawakami K. Expression of Six1 and Six4 in mouse taste buds. J Mol Histol. 2010;41:205-14 pubmed publisher
    ..We examined the expression of Six1 and Six4 mRNAs in mouse taste buds by using in situ hybridization...
  19. Soker T, Dalke C, Puk O, Floss T, Becker L, Bolle I, et al. Pleiotropic effects in Eya3 knockout mice. BMC Dev Biol. 2008;8:118 pubmed publisher
    ..Therefore, future investigations of Eya3 function should focus on aging mice. ..
  20. Chakroun I, Yang D, Girgis J, Gunasekharan A, Phenix H, Kærn M, et al. Genome-wide association between Six4, MyoD, and the histone demethylase Utx during myogenesis. FASEB J. 2015;29:4738-55 pubmed publisher
    ..The Six1 and Six4 homeodomain TFs are expressed in developing and adult muscle and Six1 is critical for embryonic and adult ..
  21. Santolini M, Sakakibara I, Gauthier M, Ribas Aulinas F, Takahashi H, Sawasaki T, et al. MyoD reprogramming requires Six1 and Six4 homeoproteins: genome-wide cis-regulatory module analysis. Nucleic Acids Res. 2016;44:8621-8640 pubmed
    ..In this study, we demonstrate that Six1 or Six4 are required for the reprogramming by MyoD of mouse embryonic fibroblasts (MEFs)...
  22. Coletta R, McCoy E, Burns V, Kawakami K, McManaman J, Wysolmerski J, et al. Characterization of the Six1 homeobox gene in normal mammary gland morphogenesis. BMC Dev Biol. 2010;10:4 pubmed publisher
    ..However, because Six1 is highly expressed in the developing mammary gland, and because it has been implicated in the expansion of mammary stem cells, targeting Six1 as an anti-cancer therapy may have unwanted side effects in the breast...
  23. Kobayashi H, Kawakami K, Asashima M, Nishinakamura R. Six1 and Six4 are essential for Gdnf expression in the metanephric mesenchyme and ureteric bud formation, while Six1 deficiency alone causes mesonephric-tubule defects. Mech Dev. 2007;124:290-303 pubmed
    ..Six1 and Six4 are the mammalian homologs of Drosophila sine oculis, and they are coexpressed in the nephrogenic mesenchyme...
  24. Zou D, Silvius D, Davenport J, Grifone R, Maire P, Xu P. Patterning of the third pharyngeal pouch into thymus/parathyroid by Six and Eya1. Dev Biol. 2006;293:499-512 pubmed
    ..Analyses of the thymus/parathyroid development in Six1-/-;Six4-/- double mutant show that both Six1 and Six4 act synergistically to control morphogenetic movements of early ..
  25. Kobayashi M, Osanai H, Kawakami K, Yamamoto M. Expression of three zebrafish Six4 genes in the cranial sensory placodes and the developing somites. Mech Dev. 2000;98:151-5 pubmed
    The homeobox gene Six4/AREC3 is a member of the vertebrate Six family of transcription factor genes. In this study we describe the cloning and expression of three zebrafish homologues of Six4/AREC3, six4.1, six4.2 and six4.3...
  26. Kawakami K, Ohto H, Takizawa T, Saito T. Identification and expression of six family genes in mouse retina. FEBS Lett. 1996;393:259-63 pubmed
    ..They are Six2, Six3 alpha and Six3 beta (which are derived from alternative splicing forms), Six5, and AREC3/Six4...
  27. Liu Y, Chu A, Chakroun I, Islam U, Blais A. Cooperation between myogenic regulatory factors and SIX family transcription factors is important for myoblast differentiation. Nucleic Acids Res. 2010;38:6857-71 pubmed publisher
    ..We have conducted a functional genomic study of the role played by SIX1 and SIX4 during the differentiation of skeletal myoblasts, a model of adult muscle regeneration...
  28. Yajima H, Motohashi N, Ono Y, Sato S, Ikeda K, Masuda S, et al. Six family genes control the proliferation and differentiation of muscle satellite cells. Exp Cell Res. 2010;316:2932-44 pubmed publisher
    ..However, the mechanisms involved in their proliferation and differentiation remain elusive. Six1 and Six4 proteins were expressed in the nuclei of myofibers of adult mice and the numbers of myoblasts positive for Six1 and ..
  29. Kahn J, Shwartz Y, Blitz E, Krief S, Sharir A, Breitel D, et al. Muscle contraction is necessary to maintain joint progenitor cell fate. Dev Cell. 2009;16:734-43 pubmed publisher
    ..In conclusion, our findings provide the missing link between progenitor cell fate determination and embryonic movement, two processes shown to be essential for correct organogenesis. ..
  30. Hu J, McGlinn E, Harfe B, Kardon G, Tabin C. Autonomous and nonautonomous roles of Hedgehog signaling in regulating limb muscle formation. Genes Dev. 2012;26:2088-102 pubmed publisher
    ..We identify neuroepithelial cell transforming gene 1 (Net1) as a downstream target and effector of Shh signaling in that context. ..
  31. Anderson C, Williams V, Moyon B, Daubas P, Tajbakhsh S, Buckingham M, et al. Sonic hedgehog acts cell-autonomously on muscle precursor cells to generate limb muscle diversity. Genes Dev. 2012;26:2103-17 pubmed publisher
    ..Thus, Shh production in the limb ZPA is essential for the spatiotemporal control of myogenesis and coordinates muscle and skeletal development by acting directly to regulate the formation of specific ventral muscles. ..
  32. Chen B, Kim E, Xu P. Initiation of olfactory placode development and neurogenesis is blocked in mice lacking both Six1 and Six4. Dev Biol. 2009;326:75-85 pubmed publisher
    ..We show here that embryos lacking both Six1 and Six4 failed to form the olfactory placode but the preplacodal region appeared to be specified as judged by the ..
  33. Fujimoto Y, Tanaka S, Yamaguchi Y, Kobayashi H, Kuroki S, Tachibana M, et al. Homeoproteins Six1 and Six4 regulate male sex determination and mouse gonadal development. Dev Cell. 2013;26:416-30 pubmed publisher
    ..Here, we report that the transcription factors Six1 and Six4 are required for male gonadal differentiation...
  34. Daou N, Lecolle S, Lefebvre S, Della Gaspera B, Charbonnier F, Chanoine C, et al. A new role for the calcineurin/NFAT pathway in neonatal myosin heavy chain expression via the NFATc2/MyoD complex during mouse myogenesis. Development. 2013;140:4914-25 pubmed publisher
    ..Altogether, our findings demonstrate that the calcineurin/NFAT pathway plays a new role in establishing the early muscle fiber type in immature myofibers during embryogenesis. ..
  35. Birol O, Ohyama T, Edlund R, Drakou K, Georgiades P, Groves A. The mouse Foxi3 transcription factor is necessary for the development of posterior placodes. Dev Biol. 2016;409:139-151 pubmed publisher
    ..Our data suggest that Foxi3 is necessary to prime pre-placodal ectoderm for the correct interpretation of inductive signals for the otic and epibranchial placodes. ..