Suzuki N et al. (2015), Identification of distal enhancers for Six2 exp...

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Int J Dev Biol 2015 Jan 01;594-6:241-6. doi: 10.1387/ijdb.140263ho.

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Identification of distal enhancers for Six2 expression in pronephros.

Suzuki N , Hirano K , Ogino H , Ochi H .

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The embryonic nephric mesenchyme contains pluripotent progenitor cells. Six2, a homeodomain transcription factor, is expressed in a subset of the nephric mesenchyme, and it functions to maintain a progenitor state by suppressing nephrogenesis. Despite the functional significance of Six2 in nephric development, its regulatory mechanisms remain unclear. To identify the cis-regulatory elements for Six2, we focused on the evolutionarily conserved sequences known as conserved noncoding sequences (CNSs) associated with the Six2 locus. Transgenic experiments using Xenopus laevis embryos revealed that three of the eight CNSs located within a 317-kb segment of the Six2 genomic locus were nephric enhancers. Motif analysis of transcription factors combined with phylogenetic footprinting revealed the enrichment of putative T-cell factor (Tcf)-, Hox-, and SWI/SNF complex helicase-like transcription factor (Hltf)- and AT-rich interactive domain 3A (Arid3a)-binding motif sequences in these enhancers.

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Species referenced: Xenopus laevis
Genes referenced: arid3a bhlhe40 ebf1 erg hltf hoxa5 jund mafg nfe2l1 pax2 rora six2 sox9 tcf7l1

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	Fig. 1. Conservation of noncoding sequences across the Six2 locus in tetrapods. (A) Schematic overview of the Six2 locus. Magenta and black boxes indicate conserved noncoding sequences and exons, respectively. (B–D) In situ hybridization analysis illustrating the expression of Six2 in Xenopus tropicalis at the stages 26, 35/36, and 43 (B,C,E). Higher magnification image of stages 35/36 embryos (D). Pn, pronephros; st, stomach; hm, head mesenchyme; ov, otic vesicle; cg, cranial ganglia.
	Fig. 2. Green fluorescent protein expression pattern driven by Six2- conserved noncoding sequences. (A–H) Transgenic Xenopus laevis embryos were generated with various reporter constructs, and their expression was analyzed using in situ hybridization. Higher magnification image of pronephric positive embryos (B’,C’,E’). Transverse section of the embryo at the level the pronephros (B’’,C’’,E’’). White arrowheads indicate expression in the pronephros. Blue arrows indicate the pronephric tubules and duct, and blue arrowheads indicate the non-glomus mesenchyme. Black and white arrows indicate expression in otic vesicle and the eye tissues, respectively
	Fig. 2. Green fluorescent protein expression pattern driven by Six2- conserved noncoding sequences. contunied, Panels G & H.