Stephen Kerridge

The tumor-suppressor and cell adhesion molecule Fat controls planar polarity via physical interactions with Atrophin, a transcriptional co-repressor

Fat is an atypical cadherin that controls both cell growth and planar polarity. Atrophin is a nuclear co-repressor that is also essential for planar polarity; however, it is not known what genes Atrophin controls in planar polarity, or how Atrophin activity is regulated during the establishment of planar polarity. We show that Atrophin binds to the cytoplasmic domain of Fat and that Atrophin mutants show strong genetic interactions with fat. We find that both Atrophin and fat clones in the eye have non-autonomous disruptions in planar polarity that are restricted to the polar border of clones and that there is rescue of planar polarity defects on the equatorial border of these clones. Both fat and Atrophin are required to control four-jointed expression. In addition our mosaic analysis demonstrates an enhanced requirement for Atrophin in the R3 photoreceptor. These data lead us to a model in which fat and Atrophin act twice in the determination of planar polarity in the eye: first in setting up positional information through the production of a planar polarity diffusible signal, and later in R3 fate determination.

The C-terminal domain of Armadillo binds to hypophosphorylated Teashirt to modulate Wingless signalling in Drosophila

Wnt signalling is a key pathway for tissue patterning during animal development. In Drosophila, the Wnt protein Wingless acts to stabilize Armadillo inside cells where it binds to at least two DNA‐binding factors which regulate specific target genes. One Armadillo‐binding protein in Drosophila is the zinc finger protein Teashirt. Here we show that Wingless signalling promotes the phosphorylation and the nuclear accumulation of Teashirt. This process requires the binding of Teashirt to the C‐terminal end of Armadillo. Finally, we present evidence that the serine/threonine kinase Shaggy is associated with Teashirt in a complex. We discuss these results with respect to current models of Armadillo/β‐catenin action for the transmission of the Wingless/Wnt pathway.

Vertebrate orthologues of the Drosophila region-specific patterning gene teashirt

In Drosophila the teashirt gene, coding for a zinc finger protein, is active in specific body parts for patterning. For example, Teashirt is required in the trunk (thorax and abdomen) tagmata of the embryo, parts of the intestine and the proximal parts of appendages. Here we report the isolation of vertebrate cDNAs related to teashirt. As in Drosophila, human and murine proteins possess three widely spaced zinc finger motifs. Additionally, we describe the expression patterns of the two murine genes. Both genes show regionalized patterns of expression, in the trunk, in the developing limbs and the gut.

Three putative murine Teashirt orthologues specify trunk structures in Drosophila in the same way as the Drosophila teashirt gene.

Drosophila teashirt (tsh) functions as a region-specific homeotic gene that specifies trunk identity during embryogenesis. Based on sequence homology, three tsh-like (Tsh) genes have been identified in the mouse. Their expression patterns in specific regions of the trunk, limbs and gut raise the possibility that they may play similar roles to tsh in flies. By expressing the putative mouse Tsh genes in flies, we provide evidence that they behave in a very similar way to the fly tsh gene. First, ectopic expression of any of the three mouse Tsh genes, like that of tsh, induces head to trunk homeotic transformation. Second, mouse Tsh proteins can rescue both the homeotic and the segment polarity phenotypes of a tsh null mutant. Third, following ectopic expression, the three mouse Tsh genes affect the expression of the same target genes as tsh in the Drosophila embryo. Fourth, mouse Tsh genes, like tsh, are able to induce ectopic eyes in adult flies. Finally, all Tsh proteins contain a motif that recruits the C-terminal binding protein and contributes to their repression function. As no other vertebrate or fly protein has been shown to induce such effects upon ectopic expression, these results are consistent with the idea that the three mouse Tsh genes are functionally equivalent to the Drosophila tsh gene when expressed in developing Drosophila embryos.

Morphogen gradients: a question of time or concentration?

Morphogens are secreted proteins that organize surrounding tissues into distinct territories and are thought to act as a function of a threshold of their concentration. Although it has been demonstrated that morphogens act directly on the cells and do not rely on secondary signalling relays, intracellular sequential induction mechanisms, which are dependent on a simple signalling instruction, have not been excluded. Here, we present an alternative model to account for the organizing properties of morphogens, and propose that initial exposure to signalling changes cell context, which in combination with continuing morphogen activity, results in the expression of novel targets.

The levels of the bancal product, a Drosophila homologue of vertebrate hnRNP K protein, affect cell proliferation and apoptosis in imaginal disc cells.

ABSTRACT We have characterized the Drosophila bancal gene, which encodes a Drosophila homologue of the vertebrate hnRNP K protein. The bancal gene is essential for the correct size of adult appendages. Reduction of appendage size in bancalmutant flies appears to be due mainly to a reduction in the number of cell divisions in the imaginal discs. Transgenes expressingDrosophila or human hnRNP K are able to rescue weakbancal phenotype, showing the functional similarity of these proteins in vivo. High levels of either human orDrosophila hnRNP K protein in imaginal discs induces programmed cell death. Expression of the antiapoptotic P35 protein suppresses this phenotype in the eye, suggesting that apoptosis is the major cellular defect caused by overexpression of K protein. Finally, the human K protein acts as a negative regulator of bancalgene expression. We propose that negative autoregulation limits the level of Bancal protein produced in vivo.

Common functions of central and posterior Hox genes for the repression of head in the trunk of Drosophila.

Hox genes are localised in complexes, encode conserved homeodomain transcription factors and have mostly been studied for their specialised functions: the formation of distinct structures along the anteroposterior axis. They probably derived via duplication followed by divergence, from a unique gene, suggesting that Hox genes may have retained a common function. The comparison of their homeodomain sequences groups Hox proteins into Anterior, Central and Posterior classes, reflecting their expression patterns in the head, trunk and tail, respectively. However, functional data supporting this classification are rare. Here, we re-examine a common activity of Hox genes in Drosophila: the repression of head in the trunk. First, we show that central and posterior Hox genes prevent the expression of the head specific gene optix in the trunk, providing a functional basis for the classification. Loss-of-function mutations of optix affect embryonic head development, whereas ectopic Optix expression strongly perturbs trunk development. Second, we demonstrate that the non-Hox genes teashirt, extradenticle and homothorax are required for the repression of optix and that Wingless signalling and Engrailed contribute to this repression. We propose that an evolutionary early function of Hox genes was to modify primitive head morphology with novel functions specialising the trunk appearing later on.

Identification of a regulatory allele of teashirt (tsh) in Drosophila melanogaster that affects wing hinge development.: An adult-specific tsh enhancer in Drosophila

A cis-acting regulatory element defined herein is required to drive teashirt (tsh) expression in the regions of the developing adult that give rise to proximal wing and haltere tissues. Loss of this expression results in the fusion of the proximal structures of the wing and halteres to the thoracic cuticle. This represents the first description of a viable adult-specific regulatory allele of tsh with a visible phenotype, and it enlarges our understanding of the expression of tsh and its function during the development of the adult.