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Homo sapiens
Homo sapiens
Mus musculus
Homo sapiens
Mus musculus
Homo sapiens
Mus musculus
Mus musculus
Homo sapiens
Mus musculus
Transcription Factor Encyclopedia  BETA
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Six3 belongs to the Six/sine oculis family of homeobox-containing transcription factors. Six3 is strongly conserved throughout metazoan evolution (see for phylogenetic tree analysis). Its homologues have been found in nematodes [1], arthropods[2], platelmintes[3], ascidians[4], chordates [5]and vertebrates[6][7][8][9][10][11][12] but not in plants, fungi or unicellular organisms. Six3 was initially isolated from a low stringency screening of a mouse embryonic brain cDNA library using Six1 cDNA as a probe [13]. Six3 contains the highly conserved 116 aa SIX domain (SD) upstream of the homeodomain (HD) [14]. Six3 expression has not been well characterized in human, however, in mouse, Six3 is expressed from early stages of development in the anterior most neural plate and then in the forebrain, retina, olfactory and lens placodes as well as the ventral hypothalamic and pituitary regions [9][13]. Later on, Six3 is expressed also in other brain regions including the olfactory bulb, cerebral cortex, striatum, thalamus, hippocampus, and midbrain areas [15][16][17]. SIX3 maps to the human chromosome 2p21. Its function is essential for the development of the anterior neural plate in humans. Mutations predicted to interfere with the function of the SIX3 protein have been found in patients affected by Holoprosencephaly Type 2 (HPE2)[18][19], a developmental defect of the forebrain and the face characterized by a variable phenotype, including craniofacial malformations, cyclopia, mid-facial defects and absence of the nasal bones. Mutations in SIX3 have been found also in humans affected by aprosencephaly/atelencephaly anophthalmia and microphthalmia[20], in agreement with the phenotype reported in mice. During late stage of retina development Six3 is expressed in the amacrine and retinal ganglion cells in different vertebrate species[21] and its activity is necessary for the specification of these cell types. In humans the protein has been also localized to the photoreceptors[22]. According to studies in other vertebrates, SIX3 controls retinal neuroblast proliferation, acting as a transcriptional repressor through the interaction with members of the Groucho family of transcriptional co-repressors. Six3 functionally interacts also with the DNA replication-inhibitor Geminin[23], which blocks the G1/S transition, controlling cell proliferation with a mechanism independent of transcriptional regulation. Six3 has been shown to interact also with a number of other transcription factors, including NeuroD, Ath1, Ath3, Ath5 as well with chromatin remodeling factors MTA1 and HDAC2 and the transcriptional co-activator EYA4[24]. Thus, Six3 seems to control gene expression in different ways and to function as a connecting link between cell signaling pathways and transcriptional regulatory networks involved in tissue specification. Indeed, Six3 regulates Wnt[25][26], and BMP[27] expression, establishing a negative feedback regulatory loop for the activation of these signaling cascades, and positively regulates the expression of Shh[19] during forebrain structure specification. Studies in teleosts have also shown that graded levels of Six3 differentially contribute to the specification of the telencephalic, retinal and hypothalimc domains by directly regulating the expression of Foxg1and Rx3[28][29] Six3 may control left/ right asymmetry through the modulation of the Nodal pathway[30][31][32][33].

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  2. Cheyette BN et al. The Drosophila sine oculis locus encodes a homeodomain-containing protein required for the development of the entire visual system. Neuron, 12(5):977-96. (PMID 7910468)
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  9. Kawakami K et al. Identification and expression of six family genes in mouse retina. FEBS Lett., 393(2-3):259-63. (PMID 8814301)
  10. Stierwald M et al. The Sine oculis/Six class family of homeobox genes in jellyfish with and without eyes: development and eye regeneration. Dev. Biol., 274(1):70-81. (PMID 15355789)
  11. Conte I and Bovolenta P. Comprehensive characterization of the cis-regulatory code responsible for the spatio-temporal expression of olSix3.2 in the developing medaka forebrain. Genome Biol., 8(7):R137. (PMID 17617896)
  12. Zhou X et al. Cloning and expression of xSix3, the Xenopus homologue of murine Six3. Mech. Dev., 91(1-2):327-30. (PMID 10704858)
  13. Oliver G et al. 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, 121(12):4045-55. (PMID 8575305)
  14. Kawakami K et al. Six family genes--structure and function as transcription factors and their roles in development. Bioessays, 22(7):616-26. (PMID 10878574)
  15. Ferran JL et al. A model of early molecular regionalization in the chicken embryonic pretectum. J. Comp. Neurol., 505(4):379-403. (PMID 17912743)
  16. Lagutin O et al. Six3 promotes the formation of ectopic optic vesicle-like structures in mouse embryos. Dev. Dyn., 221(3):342-9. (PMID 11458394)
  17. Lavado A et al. Six3 inactivation causes progressive caudalization and aberrant patterning of the mammalian diencephalon. Development, 135(3):441-50. (PMID 18094027)
  1. Solomon BD et al. A novel SIX3 mutation segregates with holoprosencephaly in a large family. Am. J. Med. Genet. A, 149A(5):919-25. (PMID 19353631)
  2. Domené S et al. Mutations in the human SIX3 gene in holoprosencephaly are loss of function. Hum. Mol. Genet., 17(24):3919-28. (PMID 18791198)
  3. Pasquier L et al. First occurrence of aprosencephaly/atelencephaly and holoprosencephaly in a family with a SIX3 gene mutation and phenotype/genotype correlation in our series of SIX3 mutations. J. Med. Genet., 42(1):e4. (PMID 15635066)
  4. Inoue T et al. Math3 and NeuroD regulate amacrine cell fate specification in the retina. Development, 129(4):831-42. (PMID 11861467)
  5. Manavathi B et al. Repression of Six3 by a corepressor regulates rhodopsin expression. Proc. Natl. Acad. Sci. U.S.A., 104(32):13128-33. (PMID 17666527)
  6. Del Bene F et al. Direct interaction of geminin and Six3 in eye development. Nature, 427(6976):745-9. (PMID 14973488)
  7. Abe Y et al. EYA4, deleted in a case with middle interhemispheric variant of holoprosencephaly, interacts with SIX3 both physically and functionally. Hum. Mutat. (PMID 19606496)
  8. Lagutin OV et al. Six3 repression of Wnt signaling in the anterior neuroectoderm is essential for vertebrate forebrain development. Genes Dev., 17(3):368-79. (PMID 12569128)
  9. Liu W et al. Neuroretina specification in mouse embryos requires Six3-mediated suppression of Wnt8b in the anterior neural plate. J. Clin. Invest., 120(10):3568-77. (PMID 20890044)
  10. McCollum CW et al. A zebrafish LMO4 ortholog limits the size of the forebrain and eyes through negative regulation of six3b and rx3. Dev. Biol., 309(2):373-85. (PMID 17692837)
  11. Beccari L et al. Sox2-mediated differential activation of Six3.2 contributes to forebrain patterning. Development, 139(1):151-64. (PMID 22096077)
  12. Sylvester JB et al. Brain diversity evolves via differences in patterning. Proc. Natl. Acad. Sci. U.S.A., 107(21):9718-23. (PMID 20439726)
  13. Inbal A et al. Six3 represses nodal activity to establish early brain asymmetry in zebrafish. Neuron, 55(3):407-15. (PMID 17678854)
  14. Seo HC et al. Expression of two zebrafish homologues of the murine Six3 gene demarcates the initial eye primordia. Mech. Dev., 73(1):45-57. (PMID 9545529)
  15. Lacbawan F et al. Clinical Spectrum of SIX3-Associated Mutations in Holoprosencephaly: Correlation between Genotype, Phenotype, and Function. J. Med. Genet. (PMID 19346217)
  16. Geng X et al. Haploinsufficiency of Six3 fails to activate Sonic hedgehog expression in the ventral forebrain and causes holoprosencephaly. Dev. Cell, 15(2):236-47. (PMID 18694563)
FIGURE 1 Six3 transcriptional vs non-transcripional activity
Six3 operates both by a transcriptional and non transcriptional mode of action to regulate gene expression and cell cycle progression, respectively.
This figure was created by the authors of this article. The authors of this article have provided the assurance that this figure constitutes their original work.