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Dpp/BMP Signaling in Flies: from Molecules to Biology

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Dpp/BMP Signaling in Flies: from Molecules to Biology G Model YSCDB 1589 1–9 ARTICLE IN PRESS Seminars in Cell & Developmental Biology xxx (2014) xxx–xxx Contents lists available at ScienceDirect Seminars in Cell & Developmental Biology j ournal homepage: www.elsevier.com/locate/semcdb 1 Review 2 Dpp/BMP signaling in flies: From molecules to biology a,∗ b c,d 3 Q1 Fisun Hamaratoglu , Markus Affolter , George Pyrowolakis a 4 Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland b 5 Growth & Development, Biozentrum, University of Basel, Basel, Switzerland c 6 Institute for Biology I, Albert-Ludwigs-University of Freiburg, Freiburg, Germany d 7 Centre for Biological Signaling Studies (BIOSS), Albert-Ludwigs-University of Freiburg, Freiburg, Germany 8 349 a r t i c l e i n f o a b s t r a c t 10 11 Article history: Decapentaplegic (Dpp), the fly homolog of the secreted mammalian BMP2/4 signaling molecules, is 12 Available online xxx involved in almost all aspects of fly development. Dpp has critical functions at all developmental stages, 13 from patterning of the eggshell to the determination of adult intestinal stem cell identity. Here, we focus 14 Keywords: on recent findings regarding the transcriptional regulatory logic of the pathway, on a new feedback 15 Drosophila regulator, Pentagone, and on Dpp’s roles in scaling and growth of the Drosophila wing. 16 Dpp © 2014 Published by Elsevier Ltd. 17 Morphogen 18 Development 19 Scaling 20 Growth 21 Patterning 22 Feedback regulation 23 Transcription 24 Pentagone 25 Brinker 26 Spalt 27 Optomotor-blind 28 Daughters-against-dpp 29 Dally 30 Silencer Element 31 SE 32 Activating Element 33 AE 35 Contents 36 1. Introduction . 00 37 2. Molecular players, transcriptional control and feedback regulation . 00 38 2.1. Transcriptional repression: Brinker and the Silencer Elements . 00 39 2.2. Transcriptional activation: the Activating Elements . 00 40 2.3. A pathway of many feedbacks . 00 41 3. Dpp and growth control . 00 42 3.1. Models in which the Dpp gradient drives proliferation (instructive) . 00 43 3.2. Models in which Dpp is permissive for growth . 00 44 3.3. Sal and Omb are critical for epithelial integrity . 00 45 3.4. Sal and Omb in proliferation control . 00 46 4. Dpp and scaling . 00 47 4.1. An expansion–repression mechanism for scaling the Dpp gradient . 00 48 4.2. Do constant thresholds determine gene expression domains? . 00 49 Acknowledgements . 00 50 References . 00 ∗ Q2 Corresponding author. Tel.: +41 612672072. E-mail address: fi[email protected] (F. Hamaratoglu). http://dx.doi.org/10.1016/j.semcdb.2014.04.036 1084-9521/© 2014 Published by Elsevier Ltd. Please cite this article in press as: Hamaratoglu F, et al. Dpp/BMP signaling in flies: From molecules to biology. Semin Cell Dev Biol (2014), http://dx.doi.org/10.1016/j.semcdb.2014.04.036 G Model YSCDB 1589 1–9 ARTICLE IN PRESS 2 F. Hamaratoglu et al. / Seminars in Cell & Developmental Biology xxx (2014) xxx–xxx 51 1. Introduction Dpp dimers (or, in some instances, heterodimers with one of the 113 other two Drosophila BMPs, Screw and Glass bottom boat) assemble 114 52 The decapentaplegic (dpp) gene was first described in 1982 by receptor complexes at the plasma membrane. Identical to verte- 115 53 Gelbart and colleagues as a gene complex; mutations in dpp pro- brate BMP signaling, receptors comprise type I and type II subunits. 116 54 duced multiple phenotypes by affecting one or several of the 15 Most effects of Dpp are mediated by the type I receptor Thickveins 117 55 imaginal discs of the Drosophila larvae [1]. Only a few years later, (Tkv) which becomes phosphorylated and activated by the type 118 56 sequencing of the dpp locus unraveled a transcript predicting dpp II receptor Punt upon ligand binding. Activated Tkv in turn phos- 119 57 to encode a member of the TGF-␤ family of signaling molecules phorylates the Drosophila Smad Mothers-against-Dpp (Mad; P-Mad 120 58 [2]. Since then, roughly 1600 papers were published on the dpp in its phosphorylated form), which associates with the co-Smad 121 59 locus and/or the function of the Dpp protein. As it turned out, Medea and accumulates in the nucleus (Fig. 1b). P-Mad/Med com- 122 60 Dpp is involved in numerous processes throughout all develop- plexes bind to GC-rich motifs in control regions of numerous genes 123 61 mental stages, from stem cell maintenance to regeneration. In and, in concert with additional transcription factors, regulate their 124 62 many instances, research on Drosophila dpp has provided important transcription. 125 63 insights into related processes in vertebrates. Nuclear responses to Dpp have been mostly analyzed in two 126 64 It is certainly for its numerous important biological roles that contexts, the establishment of the dorso-ventral axis during early 127 65 dpp has been so widely studied in flies. In the past few years, embryonic development and the larval development of the wing. 128 66 the role of Dpp, which was mostly studied in the control of pat- In both cases, Dpp establishes an activity gradient that regulates 129 67 terning of embryos and imaginal discs [3–10], has extended to expression of target genes in a concentration-dependent manner. 130 68 other developmental stages and to more novel, emerging themes Although we are still missing a thorough, genome-wide analysis of 131 69 in developmental biology. Dpp signaling has been associated with Dpp response, studies on individual target genes have revealed key 132 70 stem cell function and regulation. Some time ago already, Dpp was molecular insights in Dpp-dependent transcriptional regulation. In 133 71 found to be instrumental in maintaining self-renewal of germ line the following we focus on two important and interconnected fea- 134 72 stem cells in the stem cell niche [11] (reviewed in Refs. [12,13]). tures of Drosophila Dpp signaling, namely the ability to directly 135 73 More recently, Dpp has been implicated in size control of the repress gene transcription and the role of the transcription factor 136 74 hematopoietic niche [14], and in the control of the number of Brinker (Brk) in Smad-dependent gene regulation. 137 75 stem cells in the adult midgut of Drosophila [15]. Furthermore, Dpp 76 determines regional stem cell identity in the regenerating adult 77 Drosophila gastrointestinal tract [16]. These studies emphasize that 2.1. Transcriptional repression: Brinker and the Silencer Elements 138 78 Dpp signaling is important not only in tissue patterning, but also 79 plays an important role in tissue homeostasis. Brk is a sequence-specific transcriptional repressor that con- 139 80 Dpp controls various cellular activities, from cell division to cell tains an N-terminal homeobox-like DNA-binding domain [22–24]. 140 81 migration. It comes somewhat as a surprise, then, that in all cases The larger, C-terminal part of the protein bears interaction motifs 141 82 that have been studied in detail thus far, the effects of the loss-of- for the recruitment of multiple co-repressors, including CtBP (C- 142 83 function phenotype observed in flies is due to, or can be attributed terminal Binding Protein) and Groucho [25–27]. Importantly, Brk 143 84 to a large extend to, the regulation of transcription of downstream antagonizes Dpp-responses in numerous, if not all, processes 144 85 factors. This might be due to the approaches taken in Drosophila to (reviewed in Refs. [3,28]). During early embryogenesis, for example, 145 86 study gene (protein) function, which is tightly linked to genetics most genes that are activated by the steep dorsal-high to ventral- 146 87 and less often involves more protein-based methods such as mass low P-Mad/Med gradient in the dorsal ectoderm are simultaneously 147 88 spectrometry. In Section 2, we outline the state of the art regarding repressed ventrally by Brk. During this process, Brk is produced 148 89 the transcriptional regulation in response to Dpp signaling. Special under the control of the Dorsal morphogen gradient in the ventral 149 90 emphasis is given to the recently described feedback regulators. neurogenic ectoderm, in a region that abuts the dorsal ectoderm. 150 91 Dpp has gained broader interest in the scientific community as Although we lack direct evidence, genetic studies suggest that Brk 151 92 it represents the first bona-fide secreted morphogen [17,18]. One distributes in a gradient that is inverse to the Smad gradient [29,30]. 152 93 of the most controversial aspects of Dpp signaling is the formation While a few high Dpp threshold genes, such as race, do not require 153 94 of the Dpp gradient during wing development, which we will not Brk to establish their expression boundaries, other genes inte- 154 95 discuss in this review, but would like to direct the interested readers grate information from both Brk and P-Mad/Med [29,31–36]. Such 155 96 to a recent excellent overview of the subject [19]. Sections 3 and 4 genes are activated by P-Mad/Med complexes and simultaneously 156 97 summarize what is known about Dpp acting as a morphogen in the repressed by Brk, which establishes their ventral expression limit. 157 98 wing imaginal disk, its role in scaling and in growth control. Since Notably, and similar to what has been shown for other morphogen 158 99 research in this field is ongoing and different approaches are being gradients (such as Bicoid, for example), responses to the Dpp/Brk 159 100 pursued, no consensus has emerged yet as to the role of Dpp in gradients are anything but linear, as cis-regulatory regions of Dpp 160 101 these intriguing biological processes, and we propose that the way targets integrate additional inputs for proper expression, including 161 102 forward is to use more quantitative approaches to resolve these substantial cross-regulation between target genes [33,37,38].
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