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The Iroquois family of genes: from body building to neural patterning

Centro de Biología Molecular Severo Ochoa, CSIC and UAM, Cantoblanco, 28049 Madrid, Spain

View larger version (21K): [in a new window]   Fig. 1. Iro proteins and genomic organization of the Iro genes. All Iro proteins conform to the same structure with two strongly conserved domains: a homeodomain of the TALE class (HD) and the Iro box (ib), a motif reminiscent of the central part of the EGF repeats of the Notch receptor protein. Generally, Iro genes are chromosomally arranged in groups of three genes. Vertebrates paralogous genes are labelled with similar colours. A detailed physical map of the D. melanogaster (Dm) Iro-C is shown at the bottom of the figure. Molecular lesions associated with iro1 (chromosomal breakpoint), irorF209 (P element insertion), and iroDFM3 and mirre48 (chromosomal deletions) are indicated. Transcription units of the three Iro Drosophila genes are shown in red. Coordinates are in kb. (Data taken from Bosse et al., 2000; Gómez-Skarmeta et al., 1996; McNeill et al., 1997; Netter et al., 1998; Peters et al., 2000.)

View larger version (26K): [in a new window]   Fig. 2. Comparison of Iro early and late functions in Drosophila imaginal discs and Xenopus embryos. Top line, early functions. Iro genes are expressed in the dorsal-most regions of the early second instar eye and wing discs, respectively, and in the neural ectoderm of stage 9-10 Xenopus embryos (light pink). Absence of these early functions prevents proper development of these regions. The common functional ‘leitmotif’ is apparently the specification of large territories. Middle line, late functions. Iro genes are expressed in more resolved patterns (dark pink). Their absence removes pattern elements like sensory bristles and wing veins and probably causes transformation among different types of neurons in the vertebrate CNS. Bottom line, territories affected by early and late functions are denoted by light and dark pink, respectively. nt, section of neural tube. Iro genes are also expressed in several regions of the Drosophila embryo, other imaginal discs, and many other regions and tissues of the vertebrate embryos (Bellefroid et al., 1998; Bosse et al., 2000; Bosse et al., 1997; Calleja et al., 2000; Christoffels et al., 2000; Cohen et al., 2000; Gómez-Skarmeta et al., 1998; Goriely et al., 1999; McNeill et al., 1997; Tan et al., 1999), which suggests additional functions.

View larger version (63K): [in a new window]   Fig. 3. Iro-C promotes and organizes Drosophila eye growth. (A) The three Iro-C genes are expressed in the dorsal (D) half of the eye disc (Iro-C domain). This expression is necessary to establish the eye DV organizer (thick horizontal black line). Iro-C represses within its domain the expression of fng and the apposition of ventral (V) fng-expressing and D non-expressing cells allows the activation of the N receptor at this interface. N activity is essential for eye growth and patterning, but the nature of the signals (arrows) downstream of this activity are unknown. Iro-C- clones within the Iro-C domain allow expression of fng and establish ectopic organizers that promote development of ectopic eyes. (B,C) Conventional optic and confocal view of an eye-antenna disc bearing an Iro-C- clone (asterisk and outlined in red or white) on which the drawing in A has been modelled. (C) In the confocal view, the developing extant and ectopic eyes are visualized by Elav staining (green or yellow) that reveals developing photoreceptors. White arrowheads show positions of eye DV axes of symmetry. mf, morphogenetic furrow. (D) Ectopic eye (arrowhead), which results from an Iro-C- clone like the ones shown in B,C. (Data taken from Cavodeassi et al., 1999.)

View larger version (47K): [in a new window]   Fig. 4. Iro-C helps to specify the Drosophila notum and establishes a pattern organizer at the notum/wing hinge border. (A) Cartoon of a mature wing disc with indication of the fates of the relevant regions. Dark and light blue lines indicate compartment borders (D, dorsal; V, ventral; A, anterior; P, posterior compartments). Iro-C domain of expression is coextensive with the presumptive notum in young wing discs. This expression is necessary for the specification of the notum, as Iro-C- clones transform notum into wing hinge (Diez del Corral et al., 1999; indicated by a green H). The border of notum Iro-C-expressing and hinge Iro-C-non-expressing cells is a pattern organizing center (arrows), as revealed by the effects of Iro-C- clones on the surrounding wild-type tissue. This acquires properties of lateral notum (LN; see also below). (B) Clones of cells overexpressing Ara in the wing pouch stained with anti Ara antibody (red in the A compartment and white in the P compartment). The cells show strong affinity for each other, as indicated by the string-like shape of the clones that can establish contact even across the A/P compartment boundary (arrowhead). Blue and white, engrailed expression (data courtesy of R. Diez del Corral). (C) Iro-C- clone (iroDFM3) on which the cartoon in A has been modeled. Green: l(2)09261 marker specific for the wing, hinge and anterior lateral notum (arrowhead). This marker is not or is very weakly expressed in the rest of the presumptive notum. The presence of the Iro-C- clone (asterisk) causes the surrounding wild-type tissue to express the marker (arrow), indicating a fate transformation towards lateral notum. (Data taken from Diez del Corral et al., 1999.)

View larger version (40K): [in a new window]   Fig. 5. Early Xiro function is required for neural plate formation. (A) Drawing of a dorsal view of a Xenopus embryo at the neurula stage. Xiro overexpression on the right side (injected with Xiro1 mRNA) expands the neural plate (np). This expansion is associated with a reduction of the adjacent neural crest territory (nc). (B) Xenopus embryo injected with Xiro1 and lacZ mRNAs. Compare the size of the neural plate, as determined by expression of the Sox2 marker, in the uninjected left side with the injected right side (black arrowhead; green, X-gal-staining to reveal injected side). (C) Interference with early Xiro function using a dominant negative construct suppresses neural differentiation on the injected side (black arrowhead; brown, Myc staining, which reveals localization of dominant negative protein). (Data taken from Gómez-Skarmeta et al., 1998; Gómez-Skarmeta et al., 2001; Bellefroid et al., 1998.) White arrowheads in B,C indicate the position of the midline of the neural plate.

View larger version (41K): [in a new window]   Fig. 6. Proneural genes are expressed within the larger domains of Iro expression in both Drosophila imaginal disc and Xenopus embryos. (A) Expression of caup and sc in late third instar wing discs and a drawing showing the overlap between both patterns of expression. ara and ac expressions are indistinguishable from those of caup and sc, respectively. Proneural clusters whose presence is known to depend on Iro-C are shown in brown. Other proneural clusters are denoted in red. al, allula; DC, dorsocentral cluster; L3, L3 proneural cluster; NP, notopleural clusters; WM, wing margin. (B) Overlapping patterns of expression of Xiro1 and Xash-3 in the neural plate of the Xenopus embryos at the neurula stage. Xiro2 is co-expressed with Xiro1. Xiro3 is expressed in a similar pattern although in slightly narrower bands. In addition, both Xiro1 and Xiro2 are expressed in the prospective placode region (pc), whereas Xiro3 is expressed in lateral mesoderm. Other Xenopus proneural genes such as Xnrgr-1 are expressed in domains that partially overlap with those of Xiro genes. (Data taken from Gómez-Skarmeta et al., 1996; Gómez-Skarmeta et al., 1998; Bellefroid et al., 1998.

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