|Developmental and Signaling Pathways|
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
EGFR pathway I
EGFR pathway II
Hippo pathway I
Hippo pathway II
Hox cluster organization
Insulin signaling I
Insulin signaling II
The Insulin/Tor signaling pathway
The Melanin Biosynthetic Pathway
Myoblast fusion pathway
Nitric oxide signaling
piRNA in the soma and germline
Planar cell polarity
Presynaptic Active Zone
Postsynapse of the larval neuromuscular junction
Reward signals by excitation and inhibition of dopamine neurons
Target of rapamycin (mTOR) pathway
Wingless signaling 1
Wingless signaling 2
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).
|Hippo pathway II
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).
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).
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).
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
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).
|Insulin signaling I
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).
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).
Insulin/Tor signaling pathway
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).
Melanin Biosynthetic Pathway: Catecholamine pathway leading to sclerotization and pigmentation of the cuticle of Drosophila
Epithelial cells contacts hemolymph basally and secretes cuticle apically. Tyrosine taken up from the hemolymph is converted in epithelial cells to L-dopa by tyrosine hydroxylase (Pale) and then to dopamine by dopa decarboxylase. Some dopamine is released into the cuticle, where it is oxidized by Laccase 2 to dopamine quinone. In the presence of Yellow, dopamine quinone polymerizes to form black melanin. Some dopamine is conjugated with β-alanine by Ebony to produce N-β-alanyl dopamine, and the reverse reaction is catalysed by Tan. Upon release of N-β-alanyl dopamine into the cuticle, it is oxidized by Laccase 2 to a quinone, which mediates cuticle protein cross-linking (sclerotization) (Riedel, 2011). Riedel, F., Vorkel, D. and Eaton, S. (2011)
Riedel, F., Vorkel, D. and Eaton, S. (2011). Megalin-dependent yellow endocytosis restricts melanization in the Drosophila cuticle. Development 138: 149-158. PubMed ID: 21138977
|Myoblast fusion pathway
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).
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).
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).
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).
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).
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).
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).
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).
in the soma and germline
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,
|Postsynapse of the larval neuromuscular junction
(A) At the postsynaptic membrane, shown at the bottom, Discs large (Dlg) localizes to spectrin-actin complexes. Homophilic adhesion between Fasciclin 2 (Fas2) transmembrane proteins links the presynaptic and postsynaptic sides, with the intracellular C-terminal domains anchored to the first and second PDZ domains of Dlg. The adducin Hu-li tai shao (Hts) is in a complex with Dlg at the postsynaptic membrane, though the interaction may not be direct. Hts also binds to the lipid Phosphatidylinositol 4,5-bisphosphate (PIP2) via the MARCKS-homology domain. (B) Hts promotes the accumulation of par-1 and camkII transcripts in the muscle cytoplasm through an as of yet identified mechanism. PAR-1 and CaMKII phosphorylate Dlg. Phosphorylation disrupts Dlg postsynaptic targeting. (C) Phosphorylation translocates Hts away from the postsynaptic membrane and hinders Hts' ability to regulate Dlg localization, presumably through the control of PAR-1 and CaMKII at the transcriptional level. Phosphorylation of the MARCKS-homology domain also inhibits Hts' ability to bind to PIP2 (Wang, 2014).
Neto engages the iGluR complexes extrajunctionally and together they traffic and cluster at the synapses, opposite from the active zones marked by T-bars. Neto and the essential iGluR subunits are limiting for formation of functional iGluR complexes at the NMJ and for growth of synaptic structures (Kim, 2014).
Wang, S. J., Tsai, A., Wang, M., Yoo, S., Kim, H. Y., Yoo, B., Chui, V., Kisiel, M., Stewart, B., Parkhouse, W., Harden, N. and Krieger, C. (2014). Phospho-regulated Drosophila adducin is a determinant of synaptic plasticity in a complex with Dlg and PIP2 at the larval neuromuscular junction. Biol Open 3: 1196-1206. PubMed ID: 25416060
|Presynaptic Active Zone
Five evolutionarily conserved proteins - RIM (Drosophila Rab3 interacting molecule) , Munc13 (Drosophila unc-13), RIM-BP (Drosophila Rim-binding protein),
&alpha-liprin (Drosophila Liprin-α), and ELKS (Drosophila Bruchpilot) proteins - form the core of active zones. SYD-1 is a Rho GAP that is essential for synapse assembly in invertebrates but its functional homolog is unknown in vertebrates. RIM, Munc13, and RIM-BP are multidomain proteins composed of a string of identifiable modules, whereas α-liprin and ELKS exhibit a simpler structure. The five core active zone proteins form a single large protein complex that docks and primes synaptic vesicles, recruits Ca2+ channels to the docked and primed vesicles, tethers the vesicles and Ca2+ channels to synaptic cell-adhesion molecules, and mediates synaptic
plasticity (Südhof, 2013). Imaging of developing Drosophila glutamatergic synapses revealed that the Unc13B isoform was recruited to nascent active zones by the scaffolding proteins Syd-1 and Liprin-α, and Unc13A is positioned by Bruchpilot and Rim-binding protein complexes at maturing active zones (Bohme, 2016).
Bohme, M. A., et al. (2016). Active zone scaffolds differentially accumulate Unc13 isoforms to tune Ca2+ channel-vesicle coupling. Nat Neurosci [Epub ahead of print]. PubMed ID: 27526206
|Reward signals by excitation and inhibition of dopamine neurons
Schematic diagram of the reward circuits in the mushroom body (MB). Sugar ingestion activates multiple modulatory pathways, such as octopamine and Allatostatin A (AstA), that bidirectionally regulate distinct dopamine neurons. These dopamine neurons convey reward signals to the MB by their activation or inhibition and induce appetitive memory. A specific sub-class of these dopaminergic protocerebral anterior medial (PAM) neurons, called PAM-γ3, mediates both aversive and appetitive reinforcement through activation and suppression of their activity, respectively. Notably, transient inactivation of the basal activity of PAM-γ3 neurons substitutes for reward and induces appetitive memory formation. Interestingly, AstA, a neuropeptide that signals satiety, conveys inhibitory input onto PAM-γ3 neurons. These results highlight the bidirectional activity of defined dopaminergic neurons, which underlies encoding of behaviorally relevant appetitive and aversive values.
|Planar cell polarity
In the generation of planar cell polarity (PCP) the E3 ubiquitin ligase complex Cullin1(Cul1)/SkpA/Supernumerary limbs(Slimb) regulates the stability of one of the peripheral membrane components, Prickle (Pk). Excess Pk disrupts PCP feedback and prevents asymmetry. Pk was found to participate in negative feedback by mediating internalization of PCP complexes containing the transmembrane components Van Gogh (Vang) and Flamingo (Fmi), and that internalization is activated by oppositely oriented complexes within clusters. Pk also participates in positive feedback through an unknown mechanism promoting clustering. these results therefore identify a molecular mechanism underlying generation of asymmetry in PCP signaling
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).
|Target of rapamycin (mTOR) pathway
(A) Coincidence detector model for how mammalian mTORC1 integrates signals from nutrients and growth factors to regulate growth. The Rag GTPases promote the localization of mTORC1 to the lysosomal surface in response to nutrients, and, at the lysosome, the Rheb GTPase activates its kinase activity in response to insulin and energy levels (see Drosophila Tor, Rag A-B and Rag C-D, Tsc1, Rheb), V-ATPase and the GATOR2 component Missing oocyte. (B) Schematic showing components of the nutrient-sensing pathway upstream of mTORC1, including the many multiprotein complexes that regulate the Rag GTPases as well as the amino acid sensors Sestrin2, CASTOR1, and SLC38A9, and the SAM sensor SAMTOR (see Sabatini, 2017).
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
| Wingless signaling I
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).
|Wingless signaling II
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).
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