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Gene Review

Six1  -  sine oculis-related homeobox 1

Mus musculus

Synonyms: BB138287, Homeobox protein SIX1, Sine oculis homeobox homolog 1
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Disease relevance of Six1

  • Six1 is also expressed in the vestibuloacoustic ganglion [1].
  • Using recently generated Six1 mutant mice, we found that all Six1(+/-) mice showed some degree of hearing loss because of a failure of sound transmission in the middle ear [1].
  • Interestingly, these Six1 defects are very similar to phenotypes caused by mutations of Eya 1, which are responsible for the BOR syndrome in humans [2].
  • We conclude that Six1 overexpression reinstates an embryonic pathway of proliferation in breast cancer by up-regulating cyclin A1 [3].
  • Moreover, Ezrin is indispensable for Six1-induced metastasis and highly expressed in a panel of representative pediatric cancers [4].

High impact information on Six1

  • The identification of ezrin and Six-1 as critical regulators of metastasis in RMS provides new mechanistic and therapeutic insights into this pediatric cancer [5].
  • Overexpression of Six1 in wild-type mouse embryonic fibroblasts, but not in knockout variants lacking the cyclin A1 gene, induces cell proliferation [3].
  • Both genes are expressed in the embryonic but not the terminally differentiated mammary gland, and Six1-knockout mice show a dramatic reduction of cyclin A1 in the embryonic mammary gland [3].
  • Both of these proteins accumulate in the nucleus of C2C12 myogenic cells, and transient transfection experiments confirm that Six1 and Six4 are able to transactivate a reporter gene containing MEF3 sites [6].
  • 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 muscle-specific MEF3-binding activity in adult muscle nuclear extracts [6].

Biological context of Six1


Anatomical context of Six1

  • During inner ear development, Six1 expression was first detected in the ventral region of the otic pit and later is restricted to the middle and ventral otic vesicle within which, respectively, the vestibular and auditory epithelia form [1].
  • By contrast, Six1 expression is excluded from the dorsal otic vesicle within which the semicircular canals form [1].
  • In the developing kidney, Six1 is expressed in the uninduced metanephric mesenchyme at E10.5 and in the induced mesenchyme around the ureteric bud at E11 [9].
  • 5. At E17.5 to P0, Six1 expression became restricted to a subpopulation of collecting tubule epithelial cells [9].
  • However, this is not the consequence of a reduced ability of myogenic precursor cells to migrate into the limb buds or of an abnormal apoptosis of myoblasts lacking Six1 [8].

Other interactions of Six1

  • Six4 and Six5 single knockout (KO) mice have no developmental defects, while Six1 KO mice die at birth and show multiple organ developmental defects [7].
  • Finally, our results show that Eya1 and Six1 genetically interact during mammalian kidney development, because most compound heterozygous embryos show hypoplastic kidneys [9].
  • In contrast, Pax1 expression in all pharyngeal pouches requires both Eya1 and Six1 function [10].
  • Moreover, the expression of scleraxis is not affected in early Six1-/- mutant limbs [11].
  • The non-myogenic domain of Six1 expression establishes normally in the absence of muscle, in Pax3-/- mutant limbs [11].


  1. The role of Six1 in mammalian auditory system development. Zheng, W., Huang, L., Wei, Z.B., Silvius, D., Tang, B., Xu, P.X. Development (2003) [Pubmed]
  2. Thymus, kidney and craniofacial abnormalities in Six 1 deficient mice. Laclef, C., Souil, E., Demignon, J., Maire, P. Mech. Dev. (2003) [Pubmed]
  3. The Six1 homeoprotein stimulates tumorigenesis by reactivation of cyclin A1. Coletta, R.D., Christensen, K., Reichenberger, K.J., Lamb, J., Micomonaco, D., Huang, L., Wolf, D.M., Müller-Tidow, C., Golub, T.R., Kawakami, K., Ford, H.L. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  4. The homeoprotein six1 transcriptionally activates multiple protumorigenic genes but requires ezrin to promote metastasis. Yu, Y., Davicioni, E., Triche, T.J., Merlino, G. Cancer Res. (2006) [Pubmed]
  5. Expression profiling identifies the cytoskeletal organizer ezrin and the developmental homeoprotein Six-1 as key metastatic regulators. Yu, Y., Khan, J., Khanna, C., Helman, L., Meltzer, P.S., Merlino, G. Nat. Med. (2004) [Pubmed]
  6. Expression of myogenin during embryogenesis is controlled by Six/sine oculis homeoproteins through a conserved MEF3 binding site. Spitz, F., Demignon, J., Porteu, A., Kahn, A., Concordet, J.P., Daegelen, D., Maire, P. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  7. Six1 and Six4 homeoproteins are required for Pax3 and Mrf expression during myogenesis in the mouse embryo. Grifone, R., Demignon, J., Houbron, C., Souil, E., Niro, C., Seller, M.J., Hamard, G., Maire, P. Development (2005) [Pubmed]
  8. Altered myogenesis in Six1-deficient mice. Laclef, C., Hamard, G., Demignon, J., Souil, E., Houbron, C., Maire, P. Development (2003) [Pubmed]
  9. Six1 is required for the early organogenesis of mammalian kidney. Xu, P.X., Zheng, W., Huang, L., Maire, P., Laclef, C., Silvius, D. Development (2003) [Pubmed]
  10. Patterning of the third pharyngeal pouch into thymus/parathyroid by Six and Eya1. Zou, D., Silvius, D., Davenport, J., Grifone, R., Maire, P., Xu, P.X. Dev. Biol. (2006) [Pubmed]
  11. Six1 is not involved in limb tendon development, but is expressed in limb connective tissue under Shh regulation. Bonnin, M.A., Laclef, C., Blaise, R., Eloy-Trinquet, S., Relaix, F., Maire, P., Duprez, D. Mech. Dev. (2005) [Pubmed]
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