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Homo sapiens
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Mus musculus
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Homo sapiens
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Transcription Factor Encyclopedia  BETA
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Six6 belongs to the SIX/sine oculis (so) homeobox family of transcription factors. Six6 is strongly conserved throughout metazoan evolution (see for phylogenetic tree analysis) It was almost simultaneously described in chick, mouse and humans. This gene, also denominated Optx2 or Six9, was identified both by a conventional screening of an embryonic chick retina cDNA library using the chick Six3 as the probe, and by a computer search of the dbEST with the amino acid sequence of the human SIX3 protein. Six6 is closely related to Six3 [1][2][3][4]. Two features distinguish the Six3/ Six6 subclass from other Six genes: an insertion of four amino acids VAP(G/A)in the SD and the presence of a QKTH tetrapeptide in the N-terminal region of the homeodomain. Phylogenetic studies demonstrated that Six6 and Six3 are the mammalian homologous of Drosophila Optix.

The SIX6 gene spans 2567 bp of genomic DNA organized in two exons that are transcribed into a 1393 nucleotide long mRNA. Chromosomal mapping of SIX6 revealed that it is closely linked to SIX1 and SIX4 in human chromosome 14q22.3-q23 [4](Figure 1).

SIX6 is expressed in the anterior neural plate and later is maintained in the pituitary gland, hypothalamus and olfactory placodes as well as in the neural retina and optic stalks. In the mature retina SIX6 is localized to the amacrine and retinal ganglion cells [2][3][5][6]. Deletion of the chromosomic region encompassing the SIX6 gene has been reported in three individual affected by bilateral anophthalmia and pituitary anomalies, supporting that the SIX6 haploinsufficiency might be the cause of this phenotype[4]. Furthermore, a potentially causing missense mutation has been detected in a patient affected by congenital bilateral asymmetric microphthalmia [7]. Six6 null mice show pituitary and retinal hypoplasia, often associated with the absence of the optic chiasm and optic nerve resembling the human phenotype associated with chromosomal deletion including the SIX6 locus. Null mice are viable and thus Six6 seems not essential for survival[8]. In Xenopus and medaka fish, Six6 over-expression induces ectopic retinal tissue and eye enlargement [9][10][11]. When combined with other six transcription factors (pax6, rx1 tbx3, nr2e1, six3 and lhx2), Six6 can induce pluripotent cells from the animal pole of the Xenopus blastula to differentiate in all retinal cell classes and organize a functional eye, clearly suggesting that this gene is a basic component of the transcriptional network required to generate the vertebrate eye [12].

A number of studies have demonstrated that Six6 acts as a transcriptional repressor in association with different co-repressors, such as members of the Groucho (TLE and AES) and Dach families. Six6 directly represses the expression of cyclin inhibitors like p27Kip1 [8][13][2] and therefore is a key regulator of progenitor cell proliferation and differentiation. Recent studies in medaka fish have shown that Six6 and the neurogenic transcription factor NeuroD act in a regulatory loop that coordinate amacrine cell generation and photoreceptor terminal differentiation [14].

Six6 expression in retinal progenitor cells is regulated by the concerted action of Lhx2 and Pax6 [15].

  1. Toy J et al. The optx2 homeobox gene is expressed in early precursors of the eye and activates retina-specific genes. Proc. Natl. Acad. Sci. U.S.A., 95(18):10643-8. (PMID 9724757)
  2. López-Ríos J et al. Six9 (Optx2), a new member of the six gene family of transcription factors, is expressed at early stages of vertebrate ocular and pituitary development. Mech. Dev., 83(1-2):155-9. (PMID 10381575)
  3. Jean D et al. Six6 (Optx2) is a novel murine Six3-related homeobox gene that demarcates the presumptive pituitary/hypothalamic axis and the ventral optic stalk. Mech. Dev., 84(1-2):31-40. (PMID 10473118)
  4. Gallardo ME et al. Genomic cloning and characterization of the human homeobox gene SIX6 reveals a cluster of SIX genes in chromosome 14 and associates SIX6 hemizygosity with bilateral anophthalmia and pituitary anomalies. Genomics, 61(1):82-91. (PMID 10512683)
  5. Toy J and Sundin OH. Expression of the optx2 homeobox gene during mouse development. Mech. Dev., 83(1-2):183-6. (PMID 10381579)
  6. Conte I et al. Comparative analysis of Six 3 and Six 6 distribution in the developing and adult mouse brain. Dev. Dyn., 234(3):718-25. (PMID 15973738)
  7. Gallardo ME et al. Analysis of the developmental SIX6 homeobox gene in patients with anophthalmia/microphthalmia. Am. J. Med. Genet. A, 129A(1):92-4. (PMID 15266624)
  8. Li X et al. Tissue-specific regulation of retinal and pituitary precursor cell proliferation. Science, 297(5584):1180-3. (PMID 12130660)
  1. Zuber ME et al. Giant eyes in Xenopus laevis by overexpression of XOptx2. Cell, 98(3):341-52. (PMID 10458609)
  2. Bernier G et al. Expanded retina territory by midbrain transformation upon overexpression of Six6 (Optx2) in Xenopus embryos. Mech. Dev., 93(1-2):59-69. (PMID 10781940)
  3. López-Ríos J et al. Six3 and Six6 activity is modulated by members of the groucho family. Development, 130(1):185-95. (PMID 12441302)
  4. Viczian AS et al. Generation of functional eyes from pluripotent cells. PLoS Biol., 7(8):e1000174. (PMID 19688031)
  5. Zhu CC et al. Six3-mediated auto repression and eye development requires its interaction with members of the Groucho-related family of co-repressors. Development, 129(12):2835-49. (PMID 12050133)
  6. Conte I et al. Proper differentiation of photoreceptors and amacrine cells depends on a regulatory loop between NeuroD and Six6. Development, 137(14):2307-17. (PMID 20534668)
  7. Tétreault N et al. The LIM homeobox transcription factor Lhx2 is required to specify the retina field and synergistically cooperates with Pax6 for Six6 trans-activation. Dev. Biol., 327(2):541-50. (PMID 19146846)
FIGURE 1 Chromosomal organization of the human SIX genes.
The figure depicts the genetic and physical maps of the three chromosomal regions containing the human SIX genes. The position and 3' and 5' orientation (indicated with arrows) of the SIX genes is indicated. Distances between four polymorphic genetic markers are shown in cM. The scale in kb is different for each physical map. For chromosome 19q13.3, the positions of the DMPK gene and the (CTG)n repeat are also indicated. No other gene has been identified yet in the genomic fragments that include the SIX4-SIX1-SIX6 and the SIX2-SIX3 clusters. See reference 7 for further details. Adapted from Rodríguez de Córdoba, S. Gallardo, M.E., Lopez-Rios, J., and Bovolenta P. (2001). The human Six family of homeobox genes. Cur. Genomics, 231-242.
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.