Six2

Summary

Gene Symbol: Six2
Description: sine oculis-related homeobox 2
Alias: homeobox protein SIX2, sine oculis homeobox homolog 2, sine oculis-related homeobox 2 homolog
Species: mouse
Products:     Six2

Top Publications

  1. Esquela A, Lee S. Regulation of metanephric kidney development by growth/differentiation factor 11. Dev Biol. 2003;257:356-70 pubmed
    ..Our studies suggest that Gdf11 may be important in directing the initial outgrowth of the ureteric bud from the Wolffian duct by controlling the expression of Gdnf in the metanephric mesenchyme. ..
  2. Kiefer S, Robbins L, Rauchman M. Conditional expression of Wnt9b in Six2-positive cells disrupts stomach and kidney function. PLoS ONE. 2012;7:e43098 pubmed publisher
    During kidney development, canonical Wnt signaling activates differentiation, while the transcription factor Six2 maintains the progenitor pool...
  3. Shih H, Gross M, Kioussi C. Cranial muscle defects of Pitx2 mutants result from specification defects in the first branchial arch. Proc Natl Acad Sci U S A. 2007;104:5907-12 pubmed
    ..5. The diminutive first branchial arch of mutants could not be explained by loss of mesoderm alone, suggesting that Pitx2 contributes to the earliest specification of jaw itself. ..
  4. Karner C, Das A, Ma Z, Self M, Chen C, Lum L, et al. Canonical Wnt9b signaling balances progenitor cell expansion and differentiation during kidney development. Development. 2011;138:1247-57 pubmed publisher
    ..Interpretation of the signal is dependent, at least in part, on the activity of the transcription factor Six2. Six2-positive cells that receive the Wnt9b signal are maintained as progenitors whereas cells with reduced levels ..
  5. Torres M, Gómez Pardo E, Dressler G, Gruss P. Pax-2 controls multiple steps of urogenital development. Development. 1995;121:4057-65 pubmed
    ..These data show that Pax-2 is required for multiple steps during the differentiation of intermediate mesoderm. In addition, Pax-2 mouse mutants provide an animal model for human hereditary kidney diseases...
  6. Cain J, Islam E, Haxho F, Chen L, Bridgewater D, Nieuwenhuis E, et al. GLI3 repressor controls nephron number via regulation of Wnt11 and Ret in ureteric tip cells. PLoS ONE. 2009;4:e7313 pubmed publisher
    ..Thus, GLI3 repressor controls nephron number by regulating ureteric tip cell expression of Wnt11 and Ret. ..
  7. Couillard M, Trudel M. C-myc as a modulator of renal stem/progenitor cell population. Dev Dyn. 2009;238:405-14 pubmed publisher
    ..resulted from depletion of c-myc-positive cells in cap mesenchyme, causing a approximately 35% marked decrease of Six2- and Cited1-stem/progenitor population and of proliferation that likely impaired self-renewal...
  8. Mugford J, Sipila P, McMahon J, McMahon A. Osr1 expression demarcates a multi-potent population of intermediate mesoderm that undergoes progressive restriction to an Osr1-dependent nephron progenitor compartment within the mammalian kidney. Dev Biol. 2008;324:88-98 pubmed publisher
    ..of Osr1(+) cell fates such that at the onset of active nephrogenesis, Osr1 activity is restricted to the Six2(+) cap mesenchyme nephron progenitors...
  9. Bohnenpoll T, Bettenhausen E, Weiss A, Foik A, Trowe M, Blank P, et al. Tbx18 expression demarcates multipotent precursor populations in the developing urogenital system but is exclusively required within the ureteric mesenchymal lineage to suppress a renal stromal fate. Dev Biol. 2013;380:25-36 pubmed publisher
    ..Our study provides new insights into the molecular diversity of urogenital progenitor cells and helps to understand the specification of the ureteric mesenchymal sub-lineage...

More Information

Publications62

  1. Park J, Ma W, O Brien L, Chung E, Guo J, Cheng J, et al. Six2 and Wnt regulate self-renewal and commitment of nephron progenitors through shared gene regulatory networks. Dev Cell. 2012;23:637-51 pubmed publisher
    A balance between Six2-dependent self-renewal and canonical Wnt signaling-directed commitment regulates mammalian nephrogenesis...
  2. Xu P, Adams J, Peters H, Brown M, Heaney S, Maas R. Eya1-deficient mice lack ears and kidneys and show abnormal apoptosis of organ primordia. Nat Genet. 1999;23:113-7 pubmed
    ..In addition, our results suggest that an evolutionarily conserved Pax-Eya-Six regulatory hierarchy is used in mammalian ear and kidney development. ..
  3. Fujimura S, Jiang Q, Kobayashi C, Nishinakamura R. Notch2 activation in the embryonic kidney depletes nephron progenitors. J Am Soc Nephrol. 2010;21:803-10 pubmed publisher
    ..Here, we generated a mutant strain of mice with activated Notch2 in Six2-containing nephron progenitor cells of the metanephric mesenchyme...
  4. Brodbeck S, Besenbeck B, Englert C. The transcription factor Six2 activates expression of the Gdnf gene as well as its own promoter. Mech Dev. 2004;121:1211-22 pubmed
    ..We show here that a member of the Six family of homeobox containing transcription factors, namely Six2 activates Gdnf expression...
  5. Poladia D, Kish K, Kutay B, Hains D, Kegg H, Zhao H, et al. Role of fibroblast growth factor receptors 1 and 2 in the metanephric mesenchyme. Dev Biol. 2006;291:325-39 pubmed
    ..By in situ hybridization, regions of mutant mesenchyme near the ureteric bud(s) express Eya1 and Six1, but not Six2, Sall1, or Pax2, while the ureteric bud expresses Ret and Pax2 normally...
  6. Schönberger J, Wang L, Shin J, Kim S, Depreux F, Zhu H, et al. Mutation in the transcriptional coactivator EYA4 causes dilated cardiomyopathy and sensorineural hearing loss. Nat Genet. 2005;37:418-22 pubmed
    ..These data define unrecognized and crucial roles for Eya4-Six-mediated transcriptional regulation in normal heart function. ..
  7. Yallowitz A, Gong K, Swinehart I, Nelson L, Wellik D. Non-homeodomain regions of Hox proteins mediate activation versus repression of Six2 via a single enhancer site in vivo. Dev Biol. 2009;335:156-65 pubmed publisher
    ..b>Six2 is genetically downstream of both the Hox11 paralogous genes in the developing mammalian kidney and Hoxa2 in ..
  8. Li X, Oghi K, Zhang J, Krones A, Bush K, Glass C, et al. Eya protein phosphatase activity regulates Six1-Dach-Eya transcriptional effects in mammalian organogenesis. Nature. 2003;426:247-54 pubmed
  9. Carroll T, Park J, Hayashi S, Majumdar A, McMahon A. Wnt9b plays a central role in the regulation of mesenchymal to epithelial transitions underlying organogenesis of the mammalian urogenital system. Dev Cell. 2005;9:283-92 pubmed
    ..Together these findings suggest that Wnt9b is a common organizing signal regulating diverse components of the mammalian urogenital system...
  10. Hilliard S, Aboudehen K, Yao X, El Dahr S. Tight regulation of p53 activity by Mdm2 is required for ureteric bud growth and branching. Dev Biol. 2011;353:354-66 pubmed publisher
    ..These results demonstrate a critical and cell autonomous role for Mdm2 in the UB lineage. Mdm2-mediated inhibition of p53 activity is a prerequisite for renal organogenesis. ..
  11. Linton J, Martin G, Reichardt L. The ECM protein nephronectin promotes kidney development via integrin alpha8beta1-mediated stimulation of Gdnf expression. Development. 2007;134:2501-9 pubmed
    ..Our results thus place nephronectin and alpha8beta1 integrin in a pathway that regulates Gdnf expression and is essential for kidney development. ..
  12. Gong K, Yallowitz A, Sun H, Dressler G, Wellik D. A Hox-Eya-Pax complex regulates early kidney developmental gene expression. Mol Cell Biol. 2007;27:7661-8 pubmed
    ..we demonstrate that Hox11 paralogous proteins form a complex with Pax2 and Eya1 to directly activate expression of Six2 and Gdnf in the metanephric mesenchyme...
  13. 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
    ..g., myogenin and NeuroD3 (neurogenin1), were normal. Our results indicate that Six4 is not essential for mouse embryogenesis and suggest that other members of the Six family seem to compensate for the loss of Six4. ..
  14. Donovan M, Natoli T, Sainio K, Amstutz A, Jaenisch R, Sariola H, et al. Initial differentiation of the metanephric mesenchyme is independent of WT1 and the ureteric bud. Dev Genet. 1999;24:252-62 pubmed
    ..However, the Wolffian duct from Wt1 -/- embryos was a competent inducer of wild-type metanephric mesenchyme. ..
  15. Oliver G, Wehr R, Jenkins N, Copeland N, Cheyette B, Hartenstein V, et al. Homeobox genes and connective tissue patterning. Development. 1995;121:693-705 pubmed
    ..Six 1 and Six 2 also are expressed in skeletal and smooth muscle, respectively. These genes may participate in the patterning of the distal tendons of the limb phalanges by setting positional values along the limb axes. ..
  16. 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
    The functional activity of Six2, a member of the so/Six family of homeodomain-containing transcription factors, is required during mammalian kidney organogenesis...
  17. Reginensi A, Clarkson M, Neirijnck Y, Lu B, Ohyama T, Groves A, et al. SOX9 controls epithelial branching by activating RET effector genes during kidney development. Hum Mol Genet. 2011;20:1143-53 pubmed publisher
    ..Our results also explain the aetiology of kidney hypoplasia found in a proportion of CD patients. ..
  18. Sims Lucas S, Cusack B, Baust J, Eswarakumar V, Masatoshi H, Takeuchi A, et al. Fgfr1 and the IIIc isoform of Fgfr2 play critical roles in the metanephric mesenchyme mediating early inductive events in kidney development. Dev Dyn. 2011;240:240-9 pubmed publisher
    ..5, expressing mesenchymal markers including Eya1, Six2, Pax2, and Gdnf (unlike Fgfr1/2(Mes-/-) mice that have no obvious MM). E11...
  19. Nagalakshmi V, Ren Q, Pugh M, Valerius M, McMahon A, Yu J. Dicer regulates the development of nephrogenic and ureteric compartments in the mammalian kidney. Kidney Int. 2011;79:317-30 pubmed publisher
    ..Furthermore, an understanding of miRNA action may provide new insights into the etiology and pathogenesis of renal cyst-based kidney disease. ..
  20. Fetting J, Guay J, Karolak M, Iozzo R, Adams D, Maridas D, et al. FOXD1 promotes nephron progenitor differentiation by repressing decorin in the embryonic kidney. Development. 2014;141:17-27 pubmed publisher
  21. Kobayashi A, Valerius M, Mugford J, Carroll T, Self M, Oliver G, et al. Six2 defines and regulates a multipotent self-renewing nephron progenitor population throughout mammalian kidney development. Cell Stem Cell. 2008;3:169-81 pubmed publisher
    ..We demonstrate that the Six2-expressing cap mesenchyme represents a multipotent nephron progenitor population...
  22. Mugford J, Sipila P, Kobayashi A, Behringer R, McMahon A. Hoxd11 specifies a program of metanephric kidney development within the intermediate mesoderm of the mouse embryo. Dev Biol. 2008;319:396-405 pubmed publisher
    ..Anterior Hoxd11(+) cells activate Six2, a transcription factor required for the maintenance of metanephric tubule progenitors...
  23. Wellik D, Hawkes P, Capecchi M. Hox11 paralogous genes are essential for metanephric kidney induction. Genes Dev. 2002;16:1423-32 pubmed
    ..Eya1 expression is also intact. Six2 expression, however, is absent, as is expression of the inducing growth factor, Gdnf...
  24. Uchiyama Y, Sakaguchi M, Terabayashi T, Inenaga T, Inoue S, Kobayashi C, et al. Kif26b, a kinesin family gene, regulates adhesion of the embryonic kidney mesenchyme. Proc Natl Acad Sci U S A. 2010;107:9240-5 pubmed publisher
    ..Thus, Kif26b is essential for kidney development because it regulates the adhesion of mesenchymal cells in contact with ureteric buds. ..
  25. Xu P, Zheng W, Huang L, Maire P, Laclef C, Silvius D. Six1 is required for the early organogenesis of mammalian kidney. Development. 2003;130:3085-94 pubmed
    ..Among the six members, only the Six2 gene has been previously shown to be expressed early in kidney development, but its function is unknown...
  26. Rumballe B, Georgas K, Combes A, Ju A, Gilbert T, Little M. Nephron formation adopts a novel spatial topology at cessation of nephrogenesis. Dev Biol. 2011;360:110-22 pubmed publisher
    ..We propose that this phase of nephron formation represents an acceleration of differentiation within the cap mesenchyme due to a displacement of signals within the nephrogenic niche. ..
  27. Yallowitz A, Hrycaj S, Short K, Smyth I, Wellik D. Hox10 genes function in kidney development in the differentiation and integration of the cortical stroma. PLoS ONE. 2011;6:e23410 pubmed publisher
  28. Self M, Lagutin O, Bowling B, Hendrix J, Cai Y, Dressler G, et al. Six2 is required for suppression of nephrogenesis and progenitor renewal in the developing kidney. EMBO J. 2006;25:5214-28 pubmed
    ..In this paper, we report that functional inactivation of the homeobox gene Six2 results in premature and ectopic differentiation of mesenchymal cells into epithelia and depletion of the ..
  29. 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
    ..Accordingly, neurons from the deficient mice could not survive in culture even in the presence of neurotrophins. Our results suggest a cell-intrinsic role of Six1 and Six4 in the survival of early-generated trigeminal sensory neurons. ..
  30. 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 ..
  31. 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
  32. 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
    ..Here, we describe a novel and specific role for the homeoprotein Six2 in the growth and elongation of the cranial base...
  33. Yamamoto Shiraishi Y, Kuroiwa A. Wnt and BMP signaling cooperate with Hox in the control of Six2 expression in limb tendon precursor. Dev Biol. 2013;377:363-74 pubmed publisher
    ..The transcription factor Six2 is expressed in the developing tendons, and its expression can be traced back to a group of limb mesenchymal cells ..
  34. Chung E, Deacon P, Marable S, Shin J, Park J. Notch signaling promotes nephrogenesis by downregulating Six2. Development. 2016;143:3907-3913 pubmed
    ..We show in mice that differentiation of nephron progenitors requires downregulation of Six2, a transcription factor required for progenitor maintenance, and that Notch signaling is necessary and sufficient ..
  35. Chen S, Yao X, Li Y, Saifudeen Z, Bachvarov D, El Dahr S. Histone deacetylase 1 and 2 regulate Wnt and p53 pathways in the ureteric bud epithelium. Development. 2015;142:1180-92 pubmed publisher
    ..Together, these data indicate that Hdac1 and Hdac2 are crucial for kidney development. They perform redundant, yet essential, cell lineage-autonomous functions via p53-dependent and -independent pathways. ..
  36. Hu S, Mamedova A, Hegde R. DNA-binding and regulation mechanisms of the SIX family of retinal determination proteins. Biochemistry. 2008;47:3586-94 pubmed publisher
    ..In the present study we examined the DNA-binding specificity and mechanisms of Six2 and Six6 toward the Trex/MEF3 consensus sequence and the core tetranucleotide ATTA commonly recognized by ..
  37. Hardisty R, Erven A, Logan K, Morse S, Guionaud S, Sancho Oliver S, et al. The deaf mouse mutant Jeff (Jf) is a single gene model of otitis media. J Assoc Res Otolaryngol. 2003;4:130-8 pubmed
    ..Middle ear epithelia of Jeff mice show evidence of a chronic proliferative otitis media. The Jeff mutant should prove valuable in elucidating the underlying genetic pathways predisposing to otitis media. ..
  38. Dennis J, Kurosaka H, Iulianella A, Pace J, Thomas N, Beckham S, et al. Mutations in Hedgehog acyltransferase (Hhat) perturb Hedgehog signaling, resulting in severe acrania-holoprosencephaly-agnathia craniofacial defects. PLoS Genet. 2012;8:e1002927 pubmed publisher
    ..Future genetic studies should include HHAT as a potential candidate in the etiology and pathogenesis of HPE and its associated disorders. ..
  39. Takata N, Sakakura E, Sasai Y. IGF-2/IGF-1R signaling has distinct effects on Sox1, Irx3, and Six3 expressions during ES cell derived-neuroectoderm development in vitro. In Vitro Cell Dev Biol Anim. 2016;52:607-15 pubmed publisher
    ..Together, our results demonstrate that IGF-2/IGF-1R signaling has different effects on neural marker expression, which may influence the early regional identity of ES cell-derived neural tissues. ..
  40. Kobayashi A, Mugford J, Krautzberger A, Naiman N, Liao J, McMahon A. Identification of a multipotent self-renewing stromal progenitor population during mammalian kidney organogenesis. Stem Cell Reports. 2014;3:650-62 pubmed publisher
    The mammalian kidney is a complex organ consisting of multiple cell types. We previously showed that the Six2-expressing cap mesenchyme is a multipotent self-renewing progenitor population for the main body of the nephron, the basic ..
  41. Xu J, Wong E, Cheng C, Li J, Sharkar M, Xu C, et al. Eya1 interacts with Six2 and Myc to regulate expansion of the nephron progenitor pool during nephrogenesis. Dev Cell. 2014;31:434-47 pubmed publisher
    ..Here we show that Eya1 interacts with Six2 and Myc to control self-renewing cell activity...
  42. Yang Z, Zimmerman S, Tsunezumi J, Braitsch C, Trent C, Bryant D, et al. Role of CD34 family members in lumen formation in the developing kidney. Dev Biol. 2016;418:66-74 pubmed publisher
  43. Gao J, Kang X, Sun S, Li L, Zhang B, Li Y, et al. Transcription factor Six2 mediates the protection of GDNF on 6-OHDA lesioned dopaminergic neurons by regulating Smurf1 expression. Cell Death Dis. 2016;7:e2217 pubmed publisher
    ..In this study, we found that the expression level of transcription factor Six2 was increased in damaged DA neurons after GDNF rescue in vivo and in vitro...
  44. Chen S, Brunskill E, Potter S, Dexheimer P, Salomonis N, Aronow B, et al. Intrinsic Age-Dependent Changes and Cell-Cell Contacts Regulate Nephron Progenitor Lifespan. Dev Cell. 2015;35:49-62 pubmed publisher
    ..We provide evidence in support of a model in which intrinsic age-dependent changes affect inter-progenitor interactions that drive cessation of nephrogenesis. ..
  45. Munro D, Hohenstein P, Coate T, Davies J. Refuting the hypothesis that semaphorin-3f/neuropilin-2 exclude blood vessels from the cap mesenchyme in the developing kidney. Dev Dyn. 2017;246:1047-1056 pubmed publisher
    ..These results should provoke additional experiments to ascertain the biological significance of Sema3f/Nrp2 expression in the developing kidney. Developmental Dynamics 246:1047-1056, 2017. © 2017 Wiley Periodicals, Inc. ..
  46. Denner D, Rauchman M. Mi-2/NuRD is required in renal progenitor cells during embryonic kidney development. Dev Biol. 2013;375:105-16 pubmed publisher
    ..Markers of renal progenitor cells, Six2 and Cited1 were significantly depleted and progenitor cell proliferation was reduced...
  47. Barak H, Huh S, Chen S, Jeanpierre C, Martinovic J, Parisot M, et al. FGF9 and FGF20 maintain the stemness of nephron progenitors in mice and man. Dev Cell. 2012;22:1191-207 pubmed publisher
    ..These findings identify a long-sought-after critical component of the nephron stem cell niche and hold promise for long-term culture and utilization of these progenitors in vitro. ..
  48. 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
    We identified five cDNA clones of the Six gene family which are expressed in retina. They are Six2, Six3 alpha and Six3 beta (which are derived from alternative splicing forms), Six5, and AREC3/Six4...
  49. Oliver G, Mailhos A, Wehr R, Copeland N, Jenkins N, Gruss P. Six3, a murine homologue of the sine oculis gene, demarcates the most anterior border of the developing neural plate and is expressed during eye development. Development. 1995;121:4045-55 pubmed
    ..This region shares a homology with the distal region of mouse chromosome 17 where Six3 has been mapped. ..
  50. Sarin S, Boivin F, Li A, Lim J, Svajger B, Rosenblum N, et al. ?-Catenin overexpression in the metanephric mesenchyme leads to renal dysplasia genesis via cell-autonomous and non-cell-autonomous mechanisms. Am J Pathol. 2014;184:1395-410 pubmed publisher
    ..Together, these data support a model in which the elevation of ?-catenin in the metanephric mesenchyme results in cell-autonomous and non-cell-autonomous events that lead to the genesis of renal dysplasia. ..
  51. Hurtado R, Zewdu R, Mtui J, Liang C, Aho R, Kurylo C, et al. Pbx1-dependent control of VMC differentiation kinetics underlies gross renal vascular patterning. Development. 2015;142:2653-64 pubmed publisher
    ..These findings identify, for the first time, an in vivo transcriptional regulator of PDGFRβ, and reveal a previously unappreciated role for VMCs in systems-level vascular patterning. ..
  52. Massa F, Garbay S, Bouvier R, Sugitani Y, Noda T, Gubler M, et al. Hepatocyte nuclear factor 1? controls nephron tubular development. Development. 2013;140:886-96 pubmed publisher
    ..In addition, these studies define a novel structural and functional component of S-shaped bodies at the origin of tubule formation. ..
  53. 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
    ..We show that Six2, another transcription factor, is genetically downstream of Hoxa2...