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First published online December 8, 2004
doi: 10.1242/10.1242/dev.01539


Development 132, 3-13 (2005)
Published by The Company of Biologists 2005


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Signaling circuitries in development: insights from the retinal determination gene network

Serena J. Silver1,2,* and Ilaria Rebay1,2,{dagger}

1 Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA
2 Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA



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Fig. 1. Domain structures of the retinal determination gene network (RDGN) members. Representative members of the PAX6 (EY), EYA, SIX (SO) and DAC families from Drosophila show the domain structure of RDGN members and their functions. Numbers represent amino acid number; **, conserved MAPK phosphorylation sites in EYA. C, C terminus; DAC, Dachshund; EY, Eyeless; EYA, Eyes absent; EYA D2, EYA domain 2; GRO, Groucho; HDAC3, Histone deacetylase 3; N, N terminus; N-CoR, Nuclear corepressor; P/S/T rich, proline, serine and threonine rich region; SO, Sine oculis.

 


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Fig. 2. Retinal determination gene network (RDGN). The RDGN is expressed in a transcriptional hierarchy (black arrows), in which Twin of eyeless (TOY) leads to Eyeless (EY) expression, which leads to the expression of Sine oculis (SO), Eyes absent (EYA) and Dachshund (DAC). However, the hierarchy is not only linear, as the lower tier members EYA, SO and DAC contribute to positive feedback loops that ensure the continued expression of EY, and also physically interact with each other (pink arrows). Other RDGN members Eyegone (EYG) and OPTIX are required independently for proper eye development (see Boxes 1 and 2). Drosophila proteins are shown in green and their vertebrate homologs in blue. PAX6(5A), 5A splice isoform of PAX6.

 


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Fig. 3. Expression of signaling molecules and retinal determination gene network (RDGN) members during Drosophila eye development. (A) A schematic of the eye disc that shows morphogenetic furrow progression. The eye disc undergoes waves of differentiation as the morphogenetic furrow, which is driven by the cooperative actions of the Hedgehog (HH, blue) and Decapentaplegic (DPP, green) signaling pathways, moves from the posterior to the anterior of the eye disc. The most posterior cells have differentiated into the photoreceptor cells, while anterior cells are still proliferating. Wingless (WG) expression in the dorsal- and ventral-most anterior regions of the disc prevents eye tissue formation in that region, leading to head cuticle formation. (B) A schematic of the expression pattern of RDGN members, where the eye disc is broken up into six regions based on the level of differentiation, as described by Bessa et al. (Bessa et al., 2002Go). There are discrepancies in the literature regarding the expression pattern of Sine oculis (SO). All reports agree on the expression shown in solid red. The red hatching indicates expression reported by antibody staining (Cheyette et al., 1994Go) and in situ hybridization (Seimiya and Gehring, 2000Go) that is not seen with antibody staining by Halder et al. (Halder et al., 1998Go) or in the commonly used so-lacZ enhancer trap line, which reflects expression via a specific enhancer (Punzo et al., 2002Go). Eyegone is not shown, as it is expressed in a stripe along the dorsoventral boundary. EY, Eyeless; EYA, Eyes absent; SO, Sine oculis; DAC, Dachshund; MF, morphogenetic furrow; PPN, preproneural region.

 


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Fig. 4. Context-dependent relationships between signaling pathways and the retinal determination gene network (RDGN). Positive interactions are shown in green, negative interactions in red. Arrows represent activation or induction; blunt-end lines represent transcriptional and/or post-translational repression. DAC, DACHSHUND; DPP, Decapentaplegic; EGFR, Epidermal growth factor receptor; EYA, Eyes absent; HH, Hedgehog; SHH, Sonic hedgehog; SO, Sine oculis; WG, Wingless.

 


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Fig. 5. Differential use of the retinal determination gene network (RDGN) in muscle versus ear development. (A) A schematic of the vertebrate otic placode, which can be identified at the 4- to 13-somite stage of mouse development, shown as a cross-section through the developing embryo. HB, hindbrain; NC, notochord. The placode invaginates at embryonic day 9 (E9) to form the otic vesicle, which will close to form the otocyst. (B) The RDGN hierarchy in vertebrate muscle development is analogous to that operating in the Drosophila eye (see Fig. 1), with respect to transcriptional regulation, protein-protein interactions and positive feedback loops. However, the PAX protein that functions in muscle development is PAX3, as opposed to PAX6, which functions in the eye. (C) The functions of the RDGN during otic placode development are distinct from those operating in the muscle. Most strikingly, DAC/DACH proteins appear to function in a parallel pathway to Eyes absent (EYA)/SIX that is negatively regulated by SIX1. Feedback loops in which downstream members influence the expression of upstream components are also not apparent. Black arrows indicate transcriptional regulation, either positive or negative. Broken black arrows reflect the uncertainty in the positioning of PAX2 and PAX8 upstream of EYA2 and SIX1. Double-headed pink arrows indicate the synergistic interactions that reflect possible direct protein-protein associations.

 





© The Company of Biologists Ltd 2005