The EYA-SO/SIX complex in development and disease

Abstract

Eyes absent (EYA) and Sine oculis (SO/SIX) proteins function as transcriptional activation complexes and play essential roles in organogenesis during embryonic development in regulating cell proliferation and survival and coordination of particular differentiation programs. Mutations of the Eya and So/Six genes cause profound developmental defects in organisms as diverse as flies, frogs, fish, mice, and humans. EYA proteins also possess an intrinsic phosphatase activity, which is essential for normal development. Here, we review crucial roles of EYA and SO/SIX in development and disease in mice and humans.

Fig. 1

The EYA-SO/SIX regulatory network. a The transcriptional hierarchy among the key regulators in the fly eye discs. Feedback loops and protein-protein interactions (double-headed arrows) are indicated. b EYA and SIX form transcriptional activation complexes to control cell proliferation and survival, as well as to trigger particular differentiation programs. EYA-SIX also interact with other proteins (X), which may vary depending on distinct developmental and cellular contexts and modify the specificity of EYA-SIX function

Fig. 2

Structure of the EYA and SO/SIX family proteins. a Schematic representations of the fly EYA and mouse EYA1–4 proteins. The percentage of amino acid identity between the mouse and fly EYA are indicated. b Schematic representations of the fly SO and mouse SIX1–6 proteins showing their characteristic structural features. In addition to the Six-specific domain (SD) and the homeodomain (HD), SIX2, SIX4, and SIX5 possess a transcriptional activation domain (AD). The percentage of amino acid identity between the mouse SIX and fly SO proteins are indicated

Fig. 3

Eya1^−/−embryos lack metanephric mesenchyme (mm) and UB induction. a, b H&E-stained sections from posterior metanephric regions of E10.5 normal embryos showing the MM in wild-type embryos. Arrow points to no MM in Eya1^−/− embryos (b). c–h Whole-mount in situ hybridization showing C-ret expression in the WD and developing UB in wild-type embryos, but in Eya1^−/− mutant, the caudal WD is not induced for UB development (arrows). i, j Whole-mount in situ hybridization showing Pax2 expression in the induced MM and ureteric epithelium, but the UB development is not induced in Eya1^−/− embryos (arrow)

Fig. 4

Six1 is required for Grem1 expression in the MM. a, b A section stained by X-gal showing Six1 expression in the MM at E10.5 (a), but its expression disappears at E11.5 (b). c, d Section in situ with Grem1 probe showing its expression in the MM surrounding the UB tip in normal (c) but its expression is largely reduced in Six1^−/− embryos (d). e Schematic drawing to show that upregulation of GREM1 by SIX1 in the MM is essential to locally restrict BMP4 signaling for the initiation of branching morphogenesis. In mice, the UB formation and outgrowth is induced by GDNF-RET signaling, which is initially expressed at normal levels in Six1^−/− embryos. During this inductive period, Six1 is expressed in the MM (green). Bmp4 (red) is expressed in the mesenchyme enveloping the WD and nascent UB. Grem1 transcripts are upregulated in the MM around the UB tip region, which may locally antagonize BMP4 to enable ampulla formation of the UB and its invasion into the MM. Gdnf expression is also upregu-lated during this period to stimulate ampulla formation and establish WNT11-GDNF signaling for branching of the ampulla. In Six1^−/− embryos, the UB outgrowth is normal but the tip cells fail to be induced for ampulla formation. Instead, the tip is wrapped up by Bmp4-expressing mesenchyme, which is the cellular source for ureteral mesenchyme [122]. By responding to the signaling in the Bmp4-positive mesenchyme, the tip is induced for ureter differentiation. Our results show that the balance between the levels of BMP4 activity in the Bmp4⁺ mesenchyme and GDNF production in the MM may also be critical for UB patterning, as excessive GDNF can restore branching as well as kidney formation in Six1^−/− kidney rudiments in culture and lowering BMP4 activity in vivo can rescue branching morphogenesis and nephron formation [115] (used with permission)