Six family genes—structure and function as transcription factors and their roles in development

Abstract

The members of the Six gene family were identified as homologues of Drosophila sine oculis which is essential for compound-eye formation. The Six proteins are characterized by the Six domain and the Six-type homeodomain, both of which are essential for specific DNA binding and for cooperative interactions with Eya proteins. Mammals possess six Six genes which can be subdivided into three subclasses, and mutations of Six genes have been identified in human genetic disorders. Characterization of Six genes from various animal phyla revealed the antiquity of this gene family and roles of its members in several different developmental contexts. Some members retain conserved roles as components of the Pax-Six-Eya-Dach regulatory network, which may have been established in the common ancestor of all bilaterians as a toolbox controlling cell proliferation and cell movement during embryogenesis. Gene duplications and cis-regulatory changes may have provided a basis for diverse functions of Six genes in different animal lineages.

Cell cycle regulation of the human Six1 homeoprotein is mediated by APCCdh1

“…Immunocytochemistry of MCF7 cells transfected with these Six1 deletion mutants demonstrated that similar to full-length Six1, DHD and DCterm were primarily nuclear, whereas DNterm was largely relocalized to the cytoplasm ( Figure 5). This observation corroborates recent findings that the nuclear localization sequence (NLS) of Six2, whose N-terminus is 93% conserved to that of Six1 (Kawakami et al, 2000), resides in the N-terminus of the protein (Brodbeck et al, 2004). The DNterm construct was therefore redesigned with an NLS (NLSDNterm) and nuclear expression in MCF7 cells confirmed by immunocytochemistry (data not shown).…”

Six1controls patterning of the mouse otic vesicle

“…The Six gene family was identified as a homologue of the Drosophila sine oculis (so) and is conserved in various species (Seo et al, 1999;Kawakami et al, 2000). Six gene products are characterized by the Six domain and Six-type homeodomain, which are required for specific DNA binding activity and function as transcription factors (Kawakami et al, 1996;Spitz et al, 1998;Ohto et al, 1999;Li et al, 2002;Lagutin et al, 2003).…”

“…Six gene products are characterized by the Six domain and Six-type homeodomain, which are required for specific DNA binding activity and function as transcription factors (Kawakami et al, 1996;Spitz et al, 1998;Ohto et al, 1999;Li et al, 2002;Lagutin et al, 2003). At present, six members of the family have been identified in mammals, and all members show a spatiotemporally regulated pattern of expression during embryogenesis, suggesting their involvement in embryonic development (Seo et al, 1999;Kawakami et al, 2000). The Six gene family is known to function as a component of the Pax-Six-Eya-Dach gene network.…”

Cell Fate Determination Factor DACH1 Inhibits c-Jun–induced Contact-independent Growth

“…The eyeless, sine oculis, eyes absent, and dachshund genes are required for normal eye development, and ectopic expression of eyeless, eyes absent, and dachshund induce ectopic eye formation. This regulatory pathway, conserved among metazoans and the vertebrate homologues of eyeless (Pax6), sine oculis (Six1-6), eyes absent (Eya1-4), and dachshund (DACH1-2), contributes to organism development (Kawakami et al, 2000). The six genes encode a conserved Six and Homeo domain sequencespecific DNA binding family of transcription factors.…”