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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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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). This gene is also known as Optx2 or Six9. It was almost simultaneously described in chick, mouse and humans. It was initially identified by means of a conventional screening of an embryonic chick retina cDNA library using the chick Six3 as a probe as well as by a computer search of the dbEST using with the amino acid sequence of the human SIX3 protein. Six6 is closely related to Six3[1][2][3][4]. Like the other members of the Six/so family, Six6 is characterized by the presence of a divergent homeodomain (HD) and by an adjacent SIX domain. 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 (Figure 1). Phylogenetic studies demonstrated that Six6 and Six3 are the mammalian homologous of Drosophila Optix gene.

The mouse Six6 gene maps to chromosome 12c3 closely linked to the related Six1 and Six4 genes.

At early stages of development, Six6 expression coincides with that of Six3 in the anterior neural plate and later is maintained in the pituitary gland, hypothalamus, olfactory placodes as well as in the neural retina and optic stalk. In the differentiated retina, Six6 is expressed in the amacrine and retinal ganglion cells [2][3][5][6]. In agreement with this distribution, Six6 null mice show pituitary and retinal hypoplasia, often associated with the absence of the optic chiasm and optic nerve [7]. Null mice are viable and thus Six6 is not essential for survival. In humans, deletions of the chromosomal region encompassing the Six6 gene have been associated with bilateral clinical anophthalmia and pituitary anomalies. In Xenopus and medaka fish, Six6 over-expression induces ectopic retinal tissue and eye enlargement [8][9][10]. 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 [11].

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 [7][12][2] (Figure 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 [13].

Six6 expression in the retinal progenitor cells is regulated by the concerted action of Lhx2 and Pax6 [14].

  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. 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 Sequence comparison of Six3/6 subfamily gene
The image shows the sequence comparison of Six3 and Six6 genes from different species ranging from Human to Xenopus. Conserved residues are shown in dark-blue. The VAP(G/A) and the QKTH tetrapeptides which are distinctive for Six3 and for both Six3 and Six6 genes are boxed with a red-dashed line.
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.