logo Developmental and Signaling Pathways

Actin nucleation
Alternative splicing
Apoptosis
Axon guidance I
Axon guidance II
Cell shape change controlled by folded gastrulation
Circadian Timekeeping I
Circadian Timekeeping II
Circadian Timekeeping III
Circadian Timekeeping IV
BMP signaling I
BMP signaling II
BMP signaling III
BMP signaling IV
Ecdysteroidogenesis
EGFR pathway I
EGFR pathway II
FGF signalling
Hedgehog pathway
JAK/STAT pathway
JNK pathway
Hippo pathway I
Hippo pathway II

Hox cluster organization
Immunity I
Immunity II
Immunity III
Insulin signaling I
Insulin signaling II
The Insulin/Tor signaling pathway
The Melanin Biosynthetic Pathway
Myoblast fusion pathway
Neurogenesis I
Neurogenesis II
Neurogenesis III
Neurogenesis IV
Neurogenesis V
Nitric oxide signaling
Notch signaling
piRNA in the soma and germline
Planar cell polarity
Postsynapse of the larval neuromuscular junction
Presynaptic Active Zone
RNA Interference
Toll signaling
Wingless signaling 1
Wingless signaling 2
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Actin nucleation: The conserved Scar/Wave and Vrp1/WASp pathways for Arp2/3 activation

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




Alternative splicing

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

Apoptosis

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

Axon guidance I

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

Axon guidance II

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

Cell shape change controlled by folded gastrulation

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

Circadian Timekeeping I

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

Circadian Timekeeping II

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

Circadian Timekeeping III

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

Circadian Timekeeping IV

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

BMP signaling I

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

BMP signaling II

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 signaling III

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 IV

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

Ecdysteroidogenesis

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

EGFR pathway I

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

EGFR pathway II

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

FGF signalling

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

Hedgehog pathway

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

JAK/STAT pathway

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

JNK pathway

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

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