Crosstalk between signaling pathways is crucial for the generation of complex and varied transcriptional networks. Antagonism between the EGF-receptor (EGFR) and Notch pathways in particular is well documented, although the underlying mechanism is poorly understood. The global corepressor Groucho (Gro) and its transducin-like Enhancer-of-split (TLE) mammalian homologs mediate repression by a myriad of repressors, including effectors of the Notch, Wnt (Wg) and TGF-beta (Dpp) signaling cascades. Given that there are genetic interactions between gro and components of the EGFR pathway (ref. 9 and P.H. et al., unpublished results), we tested whether Gro is at a crossroad between this and other pathways. Here we show that phosphorylation of Gro in response to MAPK activation weakens its repressor capacity, attenuating Gro-dependent transcriptional silencing by the Enhancer-of-split proteins, effectors of the Notch cascade. Thus, Gro is a new junction between signaling pathways, enabling EGFR signaling to antagonize transcriptional output by Notch and potentially other Gro-dependent pathways.
Drosophila Groucho, like its vertebrate Transducin-like Enhancer-of-split homologues, is a corepressor that silences gene expression in numerous developmental settings. Groucho itself does not bind DNA but is recruited to target promoters by associating with a large number of DNA-binding negative transcriptional regulators. These repressors tether Groucho via short conserved polypeptide sequences, of which two have been defined. First, WRPW and related tetrapeptide motifs have been well characterized in several repressors. Second, a motif termed Engrailed homology 1 (eh1) has been found predominantly in homeodomain-containing transcription factors. Here we describe a yeast two-hybrid screen that uncovered physical interactions between Groucho and transcription factors, containing eh1 motifs, with different types of DNA-binding domains. We show that one of these, the zinc finger protein Odd-skipped, requires its eh1-like sequence for repressing specific target genes in segmentation. Comparison between diverse eh1 motifs reveals a bias for the phosphoacceptor amino acids serine and threonine at a fixed position, and a mutational analysis of Oddskipped indicates that these residues are critical for efficient interactions with Groucho and for repression in vivo. Our data suggest that phosphorylation of these phosphomeric residues, if it occurs, will down-regulate Groucho binding and therefore repression, providing a mechanism for posttranslational control of Grouchomediated repression.Negative transcriptional regulation is a strategy that has been commonly selected in evolution for setting up and maintaining gene expression patterns. A striking case in point is the process of segmentation in the early Drosophila embryo. This developmental system is regulated almost exclusively by transcription factors, many of which are repressors that silence the expression of their targets (35; reviewed in reference 57). Mutations in genes encoding these transcriptional repressors lead to the loss of repressor activity that normally restricts the expression domains of downstream genes, causing disruptions in the metameric subdivision of the fly embryo.One key principle to emerge from studies on Drosophila segmentation and on developmental processes in other model organisms is the fact that DNA-binding repressors in general do not operate on their own. Instead, they complex with nuclear coregulators, called corepressors, tethering them to promoters whose expression is subsequently blocked (43). Groucho (Gro), one such ubiquitously expressed corepressor that is highly conserved throughout evolution from worms to humans, has been shown to interact with and to potentiate the repressor function of a vast number of transcription factors, including many of those acting in segmentation (8). It is not fully understood how Gro and its Transducin-like Enhancer-of-split (TLE) mammalian homologues elicit transcriptional repression, although given that these corepressors associate with histones and bind histone deacetylases, they are likely to ...
The proper development of tissues requires morphogen activity that dictates the appropriate growth and differentiation of each cell according to its position within a developing field. Elimination of underperforming cells that are less efficient in receiving/transducing the morphogenetic signal is thought to provide a general fail-safe mechanism to avoid developmental misspecification. In the developing Drosophila wing, the morphogen Dpp provides cells with growth and survival cues. Much of the regulation of transcriptional output by Dpp is mediated through repression of the transcriptional repressor Brinker (Brk), and thus through the activation of target genes. Mutant cells impaired for Dpp reception or transduction are lost from the wing epithelium. At the molecular level, reduced Dpp signaling results in Brk upregulation that triggers apoptosis through activation of the JNK pathway. Here we show that the transcriptional co-regulator dNAB is a Dpp target in the developing wing that interacts with Brk to eliminate cells with reduced Dpp signaling through the JNK pathway. We further show that both dNAB and Brk are required for cell elimination induced by differential dMyc expression, a process that depends on reduced Dpp transduction in outcompeted cells. We propose a novel mechanism whereby the morphogen Dpp regulates the responsiveness to its own survival signal by inversely controlling the expression of a repressor, Brk, and its co-repressor, dNAB.KEY WORDS: Brinker, Dpp survival signal, Wing development, dMyc (Dm)-induced cell competition, dNAB (Drosophila Nab)
Apoptosis operates to eliminate damaged or potentially dangerous cells. This loss is often compensated by extra proliferation of neighboring cells. Studies in Drosophila imaginal discs suggest that the signal for the additional growth emanates from the dying cells. In particular, it was suggested that the initiator caspase Dronc mediates compensatory proliferation (CP) through Dp53 in wing discs. However, the exact mechanism that governs this CP remained poorly understood. We have previously shown that elimination of misspecified cells due to reduced Dpp signaling is achieved by the interaction of the corepressor NAB with the transcriptional repressor Brk, which in turn induces Jun N-terminal kinase-dependent apoptosis. Here, we performed a systematic in vivo loss-and gain-of-function analysis to study NAB-induced death and CP. Our findings indicate that the NAB primary signal activates JNK, which in turn transmits two independent signals. One triggers apoptosis through the pro-apoptotic proteins Reaper and Hid, which in turn promote activation of caspases by the apoptosome components Ark and Dronc. The other signal induces CP in a manner that is independent of the death signal, Dronc, or Dp53. Once induced, the apoptotic pathway further activates a CP response. Our data suggest that JNK is the candidate factor that differentiates between apoptosis that involves CP and apoptosis that does not.During development, apoptosis shapes structures by removing excess cells (1). Apoptosis also has an important non-developmental role of cellular proofreading: it is used to eliminate misspecified or damaged cells. In this context, apoptosis is associated with compensatory proliferation (CP), 3 a mechanism that replaces eliminated cells through stimulation of proliferation, which contributes to maintaining tissue homeostasis. Recent studies in Drosophila indicate that the signal for CP emanates from the dying cells themselves, which signal to the neighboring cells to extra proliferate to maintain tissue homeostasis and allow for proper development (2, 3). More specifically, the initiator caspase-9 homolog Dronc, a major death effector in the fly, was suggested to play an important role in promoting CP of surrounding cells (2, 4, 5). How Dronc induces CP is still unclear. One interesting candidate is the Jun N-terminal kinase signaling pathway, which was found to be activated in the dying cells and required for secretion of the mitogenic factors Wingless (Wg) and Decapentaplegic (Dpp) and stimulation of compensatory growth (3). Dronc was also shown to activate Wg and growth in response to cellular damage through activation of Drosophila p53 (Dp53) (5). Nevertheless, the exact interplay between JNK signaling, the apoptotic machinery, and compensatory growth has not been directly addressed.Dpp, a member of the TGF superfamily in Drosophila, functions in the wing primordium (wing imaginal disc (WID)) as a long-range morphogen to specify cell fates in a concentrationdependent manner. Much of the transcriptional output of Dpp is ...
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