|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
Circadian Timekeeping V
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
Postsynapse of the larval neuromuscular junction
Presynaptic Active Zone
Reward signals by excitation and inhibition of dopamine neurons
Wingless signaling 1
Wingless signaling 2
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).
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).
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,
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
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).
|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).
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).
Interlocked feedback loops.
Vrille (Vri) binds Vri/Pdp1-boxes (V/P-boxes) in the Clock (Clk) promoter, thereby repressing Clk transcription (Hardin, 2011).
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).
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.
The hierarchical dual-oscillator model of the Drosophila's circadian clock neuron network. (A) A somatic map of the clock neuron network of Drosophila. A single hemisphere (left) is shown and the various classes of clock neurons are labeled. The large ventral lateral neurons (l-LNvs) and small ventral lateral neurons (s-LNvs) express pigment-dispersing factor (PDF); all other clock neurons are PDF negative. (B) The dual-oscillator model of the lateral clock neuron network and its control of activity rhythms. The LNds and 5th s- LNv (evening (E) oscillator) control evening activity. The s-LNvs (morning (M) oscillator) control morning activity and reset the evening oscillator through daily advances (+) or delays (-), thereby maintaining clock network synchrony under constant conditions. The neuropeptides expressed by the lateral clock neurons are shown. PDF, pigment-dispersing factor; sNPF, short neuropeptide F; NPF, neuropeptide F; ITP, ion transport peptide. Only subsets of the evening oscillator neurons express PDF receptor (PDFR).
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.
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.
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).
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).
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
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).
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.
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).
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).
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).
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).
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).
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