The Actin-related protein 2/3 (Arp2/3) complex is a conserved mediator of actin polymerization. It controls the formation of branched actin networks by binding to pre-existing filaments and promoting formation of new filaments by branching. This complex is activated by actin nucleation-promoting factors (NPFs) that include Scar/Wave and WASp. Scar/Wave exists in an inactive complex with Abi, Kette and Sra1. Activation occurs upon binding of the complex to the small GTPase Rac1, releasing the VCA domain to bind to, and activate, the Arp2/3 complex. Similar to Scar/Wave, WASp is activated by protein binding to the autoinhibitory GTPase-binding domain (GBD), thereby releasing the VCA domain (Abmayr, 2012).

Abmayr, S. M. and Pavlath, G. K. (2012). Myoblast fusion: lessons from flies and mice. Development 139: 641-656. PubMed ID: 22274696

Examples of alternative splicing patterns in Drosophila genes. (A) The autosomal sex-specific splicing cascade. (B) Germ cell-specific splicing. (C) Muscle-specific splicing. IFM = indirect flight muscle. (D) Alternative splicing of Dscam. Within the cluster of exon 6, ‘acceptor’ and ‘docking’ sites are shown as black dots (see the text). (E) Alternative splicing in genes encoding cell surface molecules (F) Alternative splicing in genes encoding ion channels. (G) Alternative splicing of transcription factor genes (see Venables, 2012).

Venables, J.P., Tazi, J. and Juge, F. (2012). Regulated functional alternative splicing in Drosophila. Nucleic Acids Res 40: 1-10. PubMed ID: 21908400

Induction of apoptosis by three closely linked genes, reaper, hid and grim in Drosophila. Reaper, Hid and Grim activate cell death by inhibiting the anti-apoptotic activity of the Drosophila IAP1 (diap1) protein. In the basal state, Dark exists as an autoinhibited monomer. Elevated levels of dATP trigger assembly of the Dark apoptosome, which recruits Dronc zymogen to form a multimeric complex. Autocatalytic activation of the Dronc occurs within the multimeric complex, resulting in the release of the free Dronc caspase domain from the multimeric complex between Dronc-CARD and DARK (see Pang, 2015).

Meier, P., Finch, A. and Evan, G. (2000). Apoptosis in development. Nature 407: 796-801. PubMed ID: 11048731

Combinatorial action of LIM-homeodomain and Hox transcription factors dictate Drosophila and vertebrate motor axon guidance. Motor neurons (MNs) in Drosophila and vertebrates can be identified by the routes that they take and the muscle fields that they innervate (Butler, 2007).

Butler, S.J. and Tear, G. (2007). Getting axons onto the right path: the role of transcription factors in axon guidance. Development 134: 439-448. PubMed ID: 17185317

Schematic of the trajectories taken by commissural, ipsilateral and motor neurons in the Drosophila central nervous system (CNS). In the wild-type embryo, most CNS axons extend along a commissural pathway and cross the midline in one of two commissural axon tracts. These axons cross the midline only once. The ipsilaterally projecting axons extend on one side of the CNS only, whereas the motor neurons extend out to the periphery either on their own side of the CNS or after crossing the midline. The Drosophila CNS is bilaterally symmetrical (Araújo, 2003).

Araújo, S.J. and Tear, G. (2003). Axon guidance mechanisms and molecules: lessons from invertebrates. Nat Rev Neurosci 4: 910-922. PubMed ID: 14595402

Model of fog function in controlling cell shape change: The patterning gene twist (twi) specifies mesodermal fate of the ventral cells. These cells in turn activate transcription of folded gastrulation, resulting in the production and secretion of Fog protein from the apical side of the cell. Reception of Fog signal results in localized activation of Rho kinase which in turn activates the contractility of myosin with actin. This local source of actomyosin contractility drives myosin to the apical side of the cell. The actin-myosin cytoskeleton is tethered to the cell surface through adherens junctions. The continued contraction of apical actin-myosin exerts further force on the adherens junctions, pulling them close together, and resulting in the apical constriction of the cells and consequent gastrulation (Dawes-Hoang, 2005).

Dawes-Hoang, R. E., Parmar, K. M., Christiansen, A. E., Phelps, C. B., Brand, A. H. and Wieschaus, E. F. (2005). folded gastrulation, cell shape change and the control of myosin localization. Development 132: 4165-4178. PubMed ID: 16123312

The core photoperiod response feedback loop. Period-Timeless-Doubletime (Per-Tim-Dbt) complexes feed back to inhibit Clock-Cycle (Clk-Cyc) dependent transcription (Hardin, 2011).

Hardin, P. E. (2011). Molecular genetic analysis of circadian timekeeping in Drosophila. Adv Genet 74: 141-173. PubMed ID: 21924977

Interlocked feedback loops. Vrille (Vri) binds Vri/Pdp1-boxes (V/P-boxes) in the Clock (Clk) promoter, thereby repressing Clk transcription (Hardin, 2011).

Hardin, P. E. (2011). Molecular genetic analysis of circadian timekeeping in Drosophila. Adv Genet 74: 141-173. PubMed ID: 21924977

PER phosphorylation and translational control. Period phosphorylation increases as Per accumulates during the night, and peaks as Per is degraded in the proteasome a few hours after dawn. Dbt binds to Per and promotes Per degradation, whereas Tim binds to Per and prevents Per degradation (Hardin, 2011).

Hardin, P. E. (2011). Molecular genetic analysis of circadian timekeeping in Drosophila. Adv Genet 74: 141-173. PubMed ID: 21924977

Light-induced phase resetting mechanism. Cryptochrome (Cry) binds directly to Tim in a light-dependent manner, which irreversibly commits Tim to degradation in the proteasome.

Hardin, P. E. (2011). Molecular genetic analysis of circadian timekeeping in Drosophila. Adv Genet 74: 141-173. PubMed ID: 21924977

Dpp as an embryonic morphogen. BMP ligands Decapentaplegic (Dpp) and/or Screw (Scr), regulated by Short gastrulation (Sog), signal through the receptors Thick veins (Tkv), Punt and/or Saxophone (Sax) to the Smads Mothers against dpp (Mad) and Medea, which are transported to the nucleus where they bind to and activate or repress target genes.

O'Connor, M. B., Umulis, D., Othmer, H. G. and Blair, S. S. (2006). Shaping BMP morphogen gradients in the Drosophila embryo and pupal wing. Development 133: 183-193. PubMed ID: 16368928

Schematic model for patterning dorsal tissues in the Drosophila embryo. Tolloid (Tld) processes Short gastrulation (Sog) at the dorsal midline to release the ligand, which then binds to a receptor complex containing both Saxophone (Sax) and Thick veins (Tkv). This complex produces a synergistic high signal that activates high-level response genes such as race and leads to specification of the amnioserosa.

Shimmi, O., Umulis, D., Othmer, H. and O'Connor, M. B. (2005). Facilitated transport of a Dpp/Scw heterodimer by Sog/Tsg leads to robust patterning of the Drosophila blastoderm embryo. Cell 120: 873-886. PubMed ID: 15797386

BMP and activin signaling. The BMP ligands Dpp, Gbb and Scw, act through the type I receptors Tkv or Sax, resulting in phosphorylation of Mad, its association with the co-Smad Med, translocation of the complex into the nucleus, and regulation of gene expression. The type II receptors Put and Wit display dual specificity and function in both the BMP and activin pathways. The ligand, dActivin, signals through Babo. Phylogenetic analysis of Mav, Alp/Dawdle and Myo, does not allow their assignment to a particular pathway (see Parker, 2004).

Parker, L., Stathakis, D.G. and Arora, K. (2004). Regulation of BMP and activin signaling in Drosophila. Prog Mol Subcell Biol 34:73-101. PubMed ID: 14979665

BMP signaling in the Drosophila ovary. In the Drosophila ovary, BMP signaling from the niche represses GSC differentiation by blocking the transcription of the differentiation factor Bam. Fused (Fu) functions in concert with the E3 ligase Smurf to regulate ubiquitination and proteolysis of the BMP receptor Thickveins in cystoblasts (CBs). This regulation generates a steep gradient of BMP activity between GSCs and CBs, allowing for bam expression in CBs and concomitant differentiation (see Xia, 2010).

Xia, L., Jia, S., Huang, S., Wang, H., Zhu, Y., Mu, Y., Kan, L., Zheng, W., Wu, D., Li, X., Sun, Q., Meng, A. and Chen, D. (2010). The Fused/Smurf complex controls the fate of Drosophila germline stem cells by generating a gradient BMP response. Cell 143: 978-990. PubMed ID: 21145463

Signaling pathways that positively regulate ecdysteroidogenesis in the Prothoracic Gland (PG) in Drosophila. Prothoracicotropic hormone (PTTH) regulates the timing of metamorphosis and controls the final body size. Torso acts as PTTH receptor and transduces through mitogen-activated protein kinase (MAPK) signaling. Insulin/insulin-like growth factor (IGF) signaling (IIS) provides competence to the PG to respond to other developmental cues like PTTH when sufficient nutrients have been acquired. TGFβ/Activin seems to endow the PG to respond to developmental (PTTH) and nutritional (insulin) signals. Binding of nitric oxide (NO) to its nuclear receptor (E75) induces the expression of βFTZ-F1 leading to expression of enzymes that regulate ecdysteroidogenesis. Target of rapamycin (TOR) signaling may also interact with the PTTH pathway (see Yamanaka, 2012).

Yamanaka, N., Rewitz, K.F. and O'Connor, M.B. (2012). Ecdysone control of developmental transitions: lessons from Drosophila research. Annu Rev Entomol 58: 497-516. PubMed ID: 23072462

Feedback regulation of EGFR signalling in the Drosophila eye. Drosophila photoreceptor differentiation is assembled by a sequence of inductive signals mediated by two RTKs, EGFR and Sevenless. The Ras/Raf pathway is a phosphorylation cascade leading to activation of Pointed. Argos, a scavenger of EGF-like ligands, establishes a negative feedback loop. Reciprocal negative feedback between miR-7 and a transcriptional repressor, YAN, is induced by EGFR signaling.

Avraham, R. and Yarden, Y. (2011). Feedback regulation of EGFR signalling: decision making by early and delayed loops. Nat Rev Mol Cell Biol 12: 104-117. PubMed ID: 21252999

Model for the effect of Myopic on EGFR endocytosis in Drosophila. Upon activation of EGFR, ubiquitylation by Cbl induces EGFR internalization through clathrin-coated vesicles. These vesicles fuse with early endosomes and the EGFR is passed from the Hrs complex to the ESCRT complexes as the endosomes are transformed into multivesicular bodies (MVBs). ESCRT-III promotes EGFR degradation in endosomes. Myopic (Mop) does not itself activate EGFR, but EGFR signaling depends on the level of Mop expression (Miura, 2008).

Miura, G. I., Roignant, J. Y., Wassef, M. and Treisman, J. E. (2008). Myopic acts in the endocytic pathway to enhance signaling by the Drosophila EGF receptor. Development 135: 1913-1922. PubMed ID: 18434417

Schematic model of the canonical FGF signalling cascade in Drosophila. Activation of the FGFR leads to phosphorylation of their tyrosine kinase domains and to phosphorylation of its adaptor protein Dof. Dof protein possesses multiple clusters of tyrosine residues directing the signal towards various cascades, three of which—the Csw/Shp2, Grb2/Drk and Src64B pathways—have been proposed to contribute to MAPK activation. This route of FGF signalling is responsible for inducing gene transcription, and executing proliferative and anti-apoptotic responses (Muha, 2013).

Muha, V. and Muller, H. A. (2013). Functions and Mechanisms of Fibroblast Growth Factor (FGF) Signalling in Drosophila melanogaster. Int J Mol Sci 14: 5920-5937. PubMed ID: 23493057

The Hedgehog pathway in Drosophila and vertebrates. The Hedgehog (Hh) pathway in Drosophila and in vertebrates in the absence or presence of the Hh ligand. In Drosophila, in the absence of Hh, the Hh receptor Patched (Ptc) inhibits the cell-surface localization of Smoothened (Smo), and Cubitus interrupts (Ci) is targeted for proteolytic processing into the repressor form. In the presence of high levels of Hh ligand, Ptc inhibition is relieved and Ci is activated. In vertebrates, in the absence of Hh, Ptch1 prevents the accumulation of Smo in cilia. Gli3 is processed into a repressor form. In the presence of high levels of Hh ligand, Ptch1 inhibition is relieved and Gli proteins are activated (Huangfu, 2006).

Huangfu, D. and Anderson, K. V. (2006). Signaling from Smo to Ci/Gli: conservation and divergence of Hedgehog pathways from Drosophila to vertebrates. Development 133: 3-14. PubMed ID: 16339192

MAPK signaling is elevated in Socs36E mutant clones. A) Model of the Drosophila JAK/STAT pathway. The ligand Unpaired (Upd) is produced by hub cells and binds to and activates the receptor Domeless (Dome) on the surface of Cystoblast stem cells (CySCs). This results in activation of the JAK Hopscotch (Hop), leading to tyrosine phosphorylation of Dome. The serves as a docking site for a Stat92E, which translocates to the nucleus, and alters gene expression. Socs36E is a negative regulator of JAK/Receptor activity. B) Model of the MAPK pathway. The EGF ligand Spitz (Spi) is produced by germ line cells. Spi activates the EGF receptor (Egfr) on the surface of CySCs, which triggers the canonical MAPK pathway, ending in the activation of Pointed (Pnt), a transcriptional activator (Amoyel, 2016).

Amoyel, M., Anderson, J., Suisse, A., Glasner, J. and Bach, E. A. (2016). Socs36E Controls Niche Competition by Repressing MAPK Signaling in the Drosophila Testis. PLoS Genet 12: e1005815. PubMed ID: 26807580

The JNK pathway is a kinase cascade. In Drosophila, activation of the Jun N-terminal kinase (JNK, also called Basket (BSK)) pathway leads to phosphorylation of the transcription factors JRA (Jun-related antigen) and KAY (Kayak). puckered (puc) is a transcriptional target of the JNK pathway which negatively regulates JNK signaling. JNK cascade activation also leads to the transcriptional activation of rpr that causes the degradation of DIAP1, and ultimately, onset of apoptosis. Two JNKKs, HEP and MKK4, phorphorylate BSK at different sites and are themselves phosphorylated by JNKKKs, SLPR and dTAK1, the latter being a target for phosphorylation by MSN. DTRAF1 and DTRAF2 activate JNKKKs. TAK1-associated binding protein 2 (dTAB2) links dTRAF1 to dTAK1. The interaction between EGR/WGN (TNF/TNFR) induces JNK pathway-mediated apoptosis (Marchal, 2012).

Marchal, C., Vinatier, G., Sanial, M., Plessis, A., Pret, A.M., Limbourg-Bouchon, B., Théodore, L. and Netter, S. (2012). The HIV-1 Vpu protein induces apoptosis in Drosophila via activation of JNK signaling. PLoS One 7: e34310. PubMed ID: 22479597

Hippo signaling regulates growth in Drosophila and mice. Loss of function of Hippo (Hpo) or of Warts (Wts), two kinases that lie at the center of the Hippo pathway, results in dramatic overgrowth of imaginal discs and of corresponding adult structures. The hpo gene was thus named after its mutant adult head phenotype, which resembles the hide of the hippopotamus. In imaginal discs, the Hippo pathway primarily affects the number of cells produced and has only minor effects on tissue patterning. Thus, the Hippo pathway is a key regulator of organ growth and tissue size in Drosophila (Halder, 2011).

Halder, G. and Johnson, R. L. (2011). Hippo signaling: growth control and beyond. Development 138: 9-22. PubMed ID: 21138973

Hippo signaling regulates Drosophila intestine stem cell proliferation through multiple pathways Hpo signaling regulates intestinal stem cell (ISC) proliferation through both cell-autonomous and non–cell-autonomous mechanisms. Hpo/Wts restricts the activity of Yki in the precursor cells to inhibit ISC proliferation. This cell-autonomous mechanism could be regulated by contact between ISC and basement membrane (BM), which is disrupted by tissue-damaging reagent dextran sulfate sodium (DSS). Hpo signaling also acts in the absorptive enterocytes (ECs) to restrict the production of ligands for the JAK-STAT and EGFR pathways, thereby inhibiting ISC proliferation by limiting the activities of these two pathways. Bleomycin and possibly bacterial infection (PE) cause damage of ECs and induce ISC proliferation through Yki-dependent and Yki-independent mechanisms (Ren, 2010).

Ren, F., Wang, B., Yue, T., Yun, E. Y., Ip, Y. T. and Jiang, J. (2010).Hippo signaling regulates Drosophila intestine stem cell proliferation through multiple pathways. Proc Natl Acad Sci U S A 107: 21064-21069. PubMed ID: 21078993

Hox cluster organization in Drosophila and mouse. The Drosophila Hox genes (top) are grouped into two genomic clusters: the Antennapedia (ANT-C) and Bithorax clusters (BX-C). Expression domains of the individual Hox genes within the ANT-C and BX-C along the anteroposterior (AP) axis of the fruitfly embryo match the array of the genes along the chromosome, displaying a property termed collinearity. Mice also possess a set of Hox genes similar to those found in Drosophila and their organisation along the chromosome as well as their order of expression along the AP axis also displayed collinearity. An important difference between these two systems is that the mouse has four clusters instead of one (Mallo, 2013).

Mallo, M. and Alonso, C. R. (2013). The regulation of Hox gene expression during animal development. Development 140: 3951-3963. PubMed ID: 24046316

Immune recognition of microbial agents in Drosophila: Toll pathway and immune deficiency (Imd) pathway. The Toll and The immune deficiency (Imd) pathways control inducible immune responses to bacteria and fungi in Drosophila through systemic production of antimicrobial peptides (AMPs). In the Toll pathway, immune recognition activates a proteolytic cascade that culminates in the maturation of the cytokine Spätzle, ultimately leading to the nuclear translocation of the nuclear factor-κB (NF-κB) transcription factor Dif, to induce the expression of AMP genes such as Drosomycin. Activation of the Imd pathway leads to the nuclear translocation of the NF-κB transcription factor Relish to activate the expression of AMP genes such as Diptericin (see Buchon, 2014).

Buchon, N., Silverman, N. and Cherry, S. (2014). Immunity in Drosophila melanogaster--from microbial recognition to whole-organism physiology. Nat Rev Immunol 14: 796-810. PubMed ID: 25421701

Nucleic acid recognition and antiviral defences in Drosophila. RNA viruses often encode structured RNAs or produce double-stranded RNA (dsRNA) intermediates. These are recognized and cleaved by Dicer-2 to form virus-derived small interfering RNAs (siRNAs), which are silenced through the RNA-induced silencing complex (RISC). The PIWI-interacting RNA (piRNA) pathway protects the cell from endogenous mobile genetic elements, especially those in the germ line. Some viruses can be directly sensed by Toll-7 to induce antiviral autophagy dependent on the conserved AKT pathway (see Buchon, 2014).

Buchon, N., Silverman, N. and Cherry, S. (2014). Immunity in Drosophila melanogaster--from microbial recognition to whole-organism physiology. Nat Rev Immunol 14: 796-810. PubMed ID: 25421701

Reactive oxygen species (ROS) is another core component of the immune response in the fly intestine. ROS response is basally activated by the gut microbiota and ingested microorganisms, and strongly induced by microbial infection. Microbially derived uracil triggers the adaptor guanine-nucleotide-binding protein q subunit-α (Gαq) and phospholipase Cβ (PLCβ) to induce the synthesis of inositol-3-phosphate, which in turn mediates the release of intracellular calcium and the transcription of the oxidase-encoding gene Duox (see Buchon, 2013).

Buchon, N., Broderick, N.A. and Lemaitre, B. (2013). Gut homeostasis in a microbial world: insights from Drosophila melanogaster. Nat Rev Microbiol 11: 615-626. PubMed ID: 23893105

Feedback regulation of the insulin signaling pathway by dFOXO in Drosophila. A. The insulin receptor inactivates dFOXO through dPI3K/dAkt. Activation of d4EBP may explain growth inhibition by dFOXO, whereas activation of dInR may provide a novel transcriptionally induced feedback control mechanism for the pathway. B. When nutrients are abundant, elevated levels of DILPs are secreted to activate the dInR pathway, and the resulting downstream signaling promotes growth, in part by inhibiting dFOXO. These favorable nutrient conditions would allow growth and development. However, when nutrients are limiting, DILPs are secreted at a reduced rate, and the dInR pathway is not activated (see Puig, 2003).

Puig, O., Marr, M.T., Ruhf, M.L. and Tjian, R. (2003). Control of cell number by Drosophila FOXO: downstream and feedback regulation of the insulin receptor pathway. Genes Dev 17: 2006-2020. PubMed ID: 12893776

Endocrine interactions regulating metabolic and proliferative homeostasis in Drosophila. Tissue systems and endocrine signals mediate specific responses to dietary changes and stress to maintain homeostasis in the adult animal. Drosophila insulin-like peptides (Dilps) coordinate multiple metabolic and regenerative responses to nutritional and stress conditions (see Wang, 2014).

Wang, L., Karpac, J. and Jasper, H. (2014). Promoting longevity by maintaining metabolic and proliferative homeostasis. J Exp Biol 217: 109-118. PubMed ID: 24353210

The IIS/TOR signaling pathway in fat body and the central nervous system of Drosophila. (A) Three of the eight insulin-like proteins (ILP) are expressed in a set of neurosecretory cells in the central nervous system (CNS). These ILPs activate insulin signaling in fat body cells. (B) In the CNS two ILPs are secreted by surface glia and activate the insulin signaling pathway in the neuroblasts to regulate the growth of this tissue. The anaplastic lymphoma kinase (Alk) and its ligand, Jelly belly (Jeb) promote growth of neuroblasts in starved larvae (Koyama, 2013).

Koyama, T., Mendes, C. C. and Mirth, C. K. (2013). Mechanisms regulating nutrition-dependent developmental plasticity through organ-specific effects in insects. Front Physiol 4: 263. PubMed ID: 24133450

The fusion of myoblasts into multinucleate syncytia plays a fundamental role in muscle function, as it supports the formation of extended sarcomeric arrays, or myofibrils, within a large volume of cytoplasm. In myoblast fusion involves two cell types; founder cells/myotubes and fusion-competent myoblasts of Drosophila embryos. The represented proteins include components of the Rac1, Scar and WASp pathways and their regulators and cell-adhesion molecules. A fusion-competent myoblast migrates or extends filopodia to contact a founder cell or, in subsequent rounds of fusion, a syncytial myotube. Cell-surface adhesion molecules mediate recognition and adhesion between cells. Actin accumulates in the FCM, forming a large F-actin-based protrusion that pushes into the founder cell. A thin sheath of actin is present in the founder cell. One, or more, fusion pores form to allow mixing of cytoplasmic contents. The FCM is absorbed into the myotube, and the resulting syncytium continues additional rounds of fusion as needed (Abmayr, 2012).

Abmayr, S. M. and Pavlath, G. K. (2012). Myoblast fusion: lessons from flies and mice. Development 139: 641-656. PubMed ID: 22274696

Neuroblast temporal transitions in the embryonic CNS. Sequential transitions in neuroblast gene expression generate layered sublineage expression domains. During each temporal gene expression window, asymmetric NB divisions give rise to GMCs that are marked by the continued presence of the temporal factor that is expressed in the NB during its birth. These transcription factors are also detected in nascent postmitotic neurons and glia. Cells that express Hunchback (Hb) are positioned on the inner basal surface of the developing ganglion, and are pushed deeper into the developing neuromere upon the birth of subsequent lineages marked by expression of Kruppel, Pdm-1 (Nubbin) and Pdm-2, Castor, and Grainyhead (Brody, 2002).

Brody, T. and Odenwald, W. F. (2002). Cellular diversity in the developing nervous system: a temporal view from Drosophila. Development 129: 3763-3770. PubMed ID: 12135915

The ‘neuroblast clock’: a series of transcription factors that regulate neuroblast temporal identity. (A) Embryonic neuroblasts (NBs) consecutively express Hunchback (Hb), Seven up (Svp), Kruppel (Kr), Pdm1/2 (Pdm) and Castor (Cas); these are inherited by the ganglion mother cell (GMC). At the end of the embryonic stages, Castor-positive NBs enter quiescence. When division resumes in the larval stages, ventral nerve cord thoracic NBs transition from Castor to Svp expression (B) Larvae mutant for svp (svp−/− clones induced) do not switch off Castor expression and do not exit the cell cycle at the appropriate time the during pupal stages (see Homem, 2012).

Homem, C.C. and Knoblich, J.A. (2012).  Drosophila neuroblasts: a model for stem cell biology. Development 139: 4297-4310. PubMed ID: 23132240

Neurogenesis in the Optic Lobe: Neuroblast transitions. Medulla neurogenesis in the optic lobe depends on the sequential conversion of neuroepithelial (NE) cells to NBs. (A) Outer proliferation center (OPC) NE cells gradually convert into medulla NBs in a medial to lateral orientation. The advancement of the proneural wave is defined by Lethal of scute (L’sc) expression. (B) The gradual conversion of NE cells to NBs involves a switch from symmetric to asymmetric cell divisions. (C) The progression of the proneural wave from medial to lateral is negatively regulated by the Notch (N) pathway and positively regulated by the epidermal growth factor receptor (EGFR) pathway (Apitz, 2014).

Apitz, H. and Salecker, I. (2014). A challenge of numbers and diversity: neurogenesis in the Drosophila optic lobe. J Neurogenet 28: 233-249. PubMed ID: 24912777

Neurogenesis in the Optic Lobe: Transitions in Gene Expression. Temporal patterning of medulla NBs and Notch (N) signaling contribute to the generation of diverse neuron subtypes. (A) NE cells gradually convert into NBs. As medulla NBs age, they sequentially express the transcription factors Homothorax (Hth), Eyeless (Ey), Sloppy paired 1 and 2 (Slp), Dichaete (D), and Tailless (Tll). Each NB produces a column of medulla neurons. Progeny maintain the expression of the determinant present in the NB at the time of their birth. (B) Ey, Slp, and D are required for the transition to the next determinant. Slp, D, and Tll are necessary to repress the preceding factor in the series. Tll is sufficient but not required to repress D. (C) N-mediated binary cell fate choices further diversify lineages (Apitz, 2014).

Apitz, H. and Salecker, I. (2014). A challenge of numbers and diversity: neurogenesis in the Drosophila optic lobe. J Neurogenet 28: 233-249. PubMed ID: 24912777

Asymmetric cell division of Drosophila neuroblasts (NB) and sensory organ precursor (SOP) cells. (a) After delamination from the layer of the epithelium, the NB divides asymmetrically to generate a new NB and a ganglion mother cell (GMC). This process is guided and marked by apico-basal polarity. (b) Asymmetric division of the sensory organ precursor (SOP) cell of the Drosophila PNS, which gives rise to an anterior cell, pIIb and a posterior cell, pIIa. Aurora A and Numb are the main regulators of this division (Noatynska, 2013).

Noatynska, A., Tavernier, N., Gotta, M. and Pintard, L. (2013). Coordinating cell polarity and cell cycle progression: what can we learn from flies and worms? Open Biol 3: 130083. PubMed ID: 23926048

Nitric oxide signaling during Drosophila metamorphosis. In the prothoracic gland, nitric oxide synthase (NOS)-mediated production of NO prevents E75 function as a suppressor of DHR3, allowing DHR3 to induce βFTZ-F1 expression. βFTZ-F1 in turn promotes ecdysteroidogenesis. In peripheral tissues, E75 degradation leads to liberation of accumulated DHR3, allowing it to induce βFTZ-F1 expression  (see Venables, 2012).

Yamanaka, N. and O'Connor, M.B. (2011). Nitric oxide directly regulates gene expression during Drosophila development: need some gas to drive into metamorphosis? Genes Dev 25: 1459-1463. PubMed ID: 21764850

a. Notch signaling in Drosophila. Binding of the ligands, Delta or Serrate, to the Notch receptor leads to a series of specific cleavages of the Notch protein, and subsequently the liberation of its cytoplasmic domain (ICN). Suppressor of Hairless (Su(H)) binds to the ICN and this complex translocates to the nucleus where it activates the expression of target genes. b. In the wing imaginal disc of the third larval instar, Notch signalling is induced in two rows of cells that flank the presumptive wing margin. This causes expression of the secreted WNT-related wingless gene, which organizes gene expression in the vicinity of the wing margin. c. Segmentation of the vertebrate somitic mesoderm depends on an oscillating pattern of Notch and wingless related (Wnt)/Fibroblast growth factor (FGF) signalling that spreads along the anterior-posterior axis after being initiated in posterior-most cells (see Bier, 2005).

Bier, E. (2005). Drosophila, the golden bug, emerges as a tool for human genetics. Nat Rev Genet 6: 9-23. PubMed ID: 15630418

The Drosophila melanogaster primary PIWI-interacting RNA (piRNA) processing pathway. The primary antisense transcripts transcribed from transposons and/or the piRNA clusters are processed to piRNAs by unknown mechanisms and are loaded onto Aubergine or PIWI. piRNAs derived from the flamingo (flam) locus are exclusively loaded onto PIWI because flam is active only in ovarian somas. piRNA-induced silencing complexes produced through this mechanism act as a 'trigger' of the amplification loop (Siomi, 2011).

Siomi, M.C., Sato, K., Pezic, D. and Aravin, A.A. (2011). PIWI-interacting small RNAs: the vanguard of genome defence. Nat Rev Mol Cell Biol 12: 246-258. PubMed ID: 21427766

Small RNA silencing pathways in flies: There are three small RNA silencing pathways in flies: 1) small interfering RNA (siRNA made from double-stranded RNA precursors that are processed by Dicer-2 ), 2) microRNAs (miRNAs produced as non-coding RNA molecules that function in RNA silencing and post-transcriptional regulation of gene expression) and 3) Piwi-interacting RNAs (piRNAs linked to both epigenetic and post-transcriptional gene silencing of retrotransposons in germ line cells). dsRNA precursors generate siRNA duplexes containing guide and passenger strands that are loaded into Argonaute2. miRNAs are are cleaved by Drosha to yield short precursor miRNAs that are further processed by DCR-1. Once loaded into AGO1, the miRNA strand guides translational repression of target RNAs. Antisense piRNAs are are preferentially loaded into Piwi or Aubergine and probably direct cleavage of transposon mRNA or chromatin modification at transposon loci (Ghildiyal, 2009).

Ghildiyal, M. and Zamore, P.D. (2009). Small silencing RNAs: an expanding universe. Nat Rev Genet 10: 94-108. PubMed ID: 21764850

Comparison of Drosophila immune deficiency (imd), Toll, and mammalian TLR signaling pathways. The Imd pathway is activated by DAP-type PGN binding of the PGRP-LC dimer and ultimately leads to the phosphorylation and activation of Relish and AP-1, which activate the transcription of AMP and stress genes, respectively. The Toll pathway is activated by Spz leading to the nuclear translocation of Dif. Mammalian TLRs are activated by bacterial-, viral-, and self-derived products. TLR activation ultimately results in activation and nuclear translocation of NF-κB and AP-1 (see Valanne, 2011).

Valanne, S., Wang, J.H. and Rämet, M. (2011). The Drosophila Toll signaling pathway. J Immunol 186: 649-656. PubMed ID: 21209287

Canonical Wnt signaling pathway in Drosophila. Binding of Wingless (Wg) to Frizzled (Fz) leads to Axin degradation, thus allowing Armadillo (Arm) accumulation and its subsequent translocation to the nucleus where it binds Tcf, displaces the Groucho co-repressor, and this leads to target gene expression (see Bejsovec, 2013).

Bejsovec, A. (2013). Wingless/Wnt signaling in Drosophila: the pattern and the pathway. Mol Reprod Dev 80: 882-894. PubMed ID: 24038436

The role of negative feedback inhibitors in Wingless (Wg) signaling. Drosophila Wg pathway components include the receptor Frizzled 2 (Fz2), Dishevelled (Dsh), Armadillo (Arm) and Pangolin (dTcf). Wg signaling is controlled by a number of induced inhibitors including Naked (Nkd) and Wingful/Notum (Wf). Wg also regulates Nemo expression and Nemo in turn can antagonize Wg during wing patterning (Zeng, 2004).

Zeng, Y. A. and Verheyen, E. M. (2004). Nemo is an inducible antagonist of Wingless signaling during Drosophila wing development. Development 131: 2911-2920. PubMed ID: 15169756