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Headless flies generated by developmental pathway interference

Renjie Jiao^*, Michael Daube, Hong Duan, Yu Zou, Erich Frei and Markus Noll

Institute for Molecular Biology, University of Zürich, Winterthurerstr. 190, CH-8057 Zürich, Switzerland
^* Present address: Institute of Veterinary Biochemistry, University of Zürich, Winterthurerstr. 190, CH-8057 Zürich, Switzerland
Present address: Department of Medicine, Division of Cardiology, Albert Einstein College of Medicine, Bronx, NY 10461, USA

View larger version (88K): [in a new window]   Fig. 1. Interference of ectopic Poxn with D-Pax2 functions in eye development. Left eyes of flies of the genotype indicated in each panel are shown in scanning electron micrographs. Note that the phenotype produced by ectopic Poxn expression under the control of the sev enhancer (A) is similar to that of spapol mutants (B), but stronger than that generated by ectopic Poxn expressed under the indirect control of the spa enhancer of D-Pax2 (G). Reducing D-Pax2 expression during eye development in heterozygous (C,H) or homozygous spapol (D) backgrounds enhances the phenotypes produced by ectopic Poxn, whereas raising D-Pax2 levels by an additional copy of D-Pax2 under the control of the sev (E) or spa (F) enhancer rescues the sev-Poxn phenotype to wild type (compare with Fig. 3D).

View larger version (80K): [in a new window]   Fig. 2. Ectopic Pax proteins in eye-antennal disc generate headless flies. Scanning electron micrographs of the anterior portion of ey-Gal4/+; UAS-Gsb-1/+ (A-D), homozygous eyD (E) and wild-type flies (F) are compared. The interference with head development of ectopic Gsb (D-Pax2, Poxn, Poxm, or Prd) in eye-antennal discs results in ‘headless’ flies of variable expressivity. Representative phenotypes of the four phenotypic classes are shown: (A) class I, all head structures derived from eye-antennal disc, including eye, antenna, head capsule and maxillary palps, are missing, only the proboscis, largely derived from the clypeolabral (cl) and labial disc (lbl), is present; (B) class II, most head structures and both eyes and antennae absent; (C) class III, large parts of head and both eyes missing, portions of one or both antennae (ant) present; and (D) class IV, most of head and one or both eyes of reduced size present. Note that flies homozygous for the strong eyD allele also exhibit a headless phenotype (E). ant, antenna; cl, clypeus; lbl, labellum; lr, labrum; mpl, maxillary palp.

View larger version (178K): [in a new window]   Fig. 3. Headless flies result from interference with ey functions, which depends on DNA-binding activities different from that of Ey. Left eyes of flies are shown in scanning electron micrographs. (A) UAS-Ey rescues the headless phenotype in ey-Gal4/UAS-Gsb-7; UAS-Ey/+ flies almost completely to a small-eye phenotype. (B) A different small-eye phenotype is produced in ey-Gal4/+; UAS-Ey/+ flies. (C) ey-Gal4/+; UAS-GE-8/+ flies, which carry mutations in amino acids 42 (Q mutated to I), 44 (R to Q) and 47 (H to N) in the paired domain of UAS-Gsb changing its DNA-binding specificity to that of the Ey paired domain, exhibit little or no interference with ey functions and display, in four out of six lines, a phenotype similar to wild type (D) or, in two lines, a weak phenotype similar to ey-Gal4/+; UAS-Ey/+ flies (B).

View larger version (11K): [in a new window]   Fig. 4. Mechanisms of interference with Ey functions through ectopic Pax proteins. Four mechanisms by which ectopic Pax proteins could interfere with the developmental program depending on Ey functions in eye-antennal discs are illustrated. In the first model, Pax proteins repress ey transcription either directly by blocking its enhancer (I), or indirectly by interfering with genes or their products required for ey activation (not shown). In the second (II) and third model (III), Pax proteins inhibit transcription of Ey target genes (X), activated in the wild type (wt) by Ey and a set of transcription factors (C), in a dominant negative manner. By contrast, in the fourth model (IV), ectopic Pax proteins do not interfere with transcription of ey or that of the targets of its product. Rather by altering the regulation of a set of target genes (Y), in combination with a set of transcription factors (D), ectopic Pax proteins activate a genetic program that interferes with the normal progression of the developmental pathway dependent on ey. While our results exclude models I-III and favor model IV of ‘developmental pathway interference’ activated by ectopic Pax proteins or other ectopic transcription factors, they do not rule out models I-III for few specific transcription factors not examined in this study.

View larger version (21K): [in a new window]   Fig. 5. Generation of headless phenotype depends on functional paired domain and transactivation domain in ectopic Gsb. The ability of mutated Gsb proteins, which are encoded by the transgenes listed in the left column and whose structure is shown schematically in the middle column, to generate class I-IV headless phenotypes is indicated in the right column. For a detailed explanation, see text.

View larger version (85K): [in a new window]   Fig. 6. Partial rescue by CycE or Myc of headless phenotype caused by developmental pathway interference. The rescue effect of D-Myc and D-CycE on adult head development, inhibited by ectopic expression of transcription factors under the control of ey-Gal4, is shown in scanning electron micrographs (anterior is to the left). (A,B) UAS-D-Myc rescues head (A) and eye development (B) in ey-Gal4/UAS-Gsb-7; UAS-D-Myc/+ flies. (C,D) Complete (C) and partial (D) rescue of head and eye development by UAS-D-CycE in ey-Gal4/UAS-Gsb-7; UAS-D-CycE/+ flies. (E-G) Partial (E) and nearly complete (F,G) rescue of head and eye development by UAS-D-CycE to adults that eclosed spontaneously in ey-Gal4/+; UAS-Dac/UAS-D-CycE (E), ey-Gal4/+; UAS-Poxm/UAS-D-CycE (F), and ey-Gal4/+; UAS-Prd-1/UAS-D-CycE flies (G). (H) Complete rescue of head and eye development by UAS-D-Myc in ey-Gal4/+; UAS-D-Pax2-1/UAS-D-Myc flies. Flies shown developed at room temperature (22°C), except for E, which developed at 25°C.