Morphogen gradient, cascade, signal transduction
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Transcript of Morphogen gradient, cascade, signal transduction
Morphogen gradient, cascade, signal transduction
Maternal effect genes
Zygotic genesSyncytial blastoderm
Cellular blastoderm
Homeotic selector genesSimilar signal into different structures—
Different interpretation—controlled by Hox genes
Metamorphosis
Homeotic transformation of the wing and haltereHomeotic genes—mutated into homeosis transformation
As positional identity specifiers
Mutant-antennapedia—into legBithorax-haltere into wing
Imaginal discs and adult thoracic appendages
Bithorax mutation—Ubx misexpressed T3 into T2 –anterior haltere into Anterior wing
Postbithorax muation (pbx)—Regulatory region of the Ubx—Posterior of the haltere into wing
Homeotic selector genes
Each segment unique identity—master regulator genesHomeotic selector genes—control other genes-required throughout development
Spatial& temporal expression—mechanism of controlling of these genes
Fig. 5-37
Regulatory elements
The spatial pattern of expression of genes of the bithorax complex
Bithorax—Ultrabithorax –5-12 Abdominal-A—7-13 Abdominal-B—10-13
Bithorax mutant –PS 4 default state
Fig. 5-39
Bithorax mutant –PS 4 default state+Ubx—5,6+Abd-A—7,8,9+Abd-B—10Combinatorial manner
Lack Ubx—5,6 to 4 also 7-14 thorax structure in the abdomen
Hox—gap, pair-rule for the first 4 hours, then polycomb (repression), and Trithorax (activation)
Fig. 5-39
Segmental identity of imaginal disc
Antennapedia—expressed in legs, but not in antennaIf in head, antennae into legs
Hth (homothorax) and Dll (distal-less)—expressed in antennae and legIn antenna: as selector to specify antennaIn leg: antennapedia prevents Hth and Dll acting together
Dominant antennapedia mutant (gene on)—blocks Hth and Dll in antennae disc, so leg formsNo Hth, antenna into leg
Gene expression in the visceral mesoderm patterns the underlying gut endodermPatterning of the endoderm
Labial—antennapedia complex
Fig. 5-40
Fly and mouse/human genomes of homeotic genes
Homeobox and homeodomain
Expression pattern and the location on chromosome
Mutation in HoxD13—synpolydactylyExtra digits & interphalangeal webbing (hetero)Similar but more severe & bony malformation of hands, wrists (Homo)
Before fertilization ligand immobilized
Small quantities—bound to torso at the poleslittle left to diffuse
Anterior/posterior extremities
Terminal structure-acron., telson, most posterior abdominal segment
Torso---receptor tyrosine kinaseLigand---trunk
Fig. 5-7
Torso signaling
Groucho: repressorHuckenbein, tailless are released from transcriptional suppression
Egg chamber formation(oogenesis)
Signals from older to younger egg chambers
Red arrow: Delta-Notch induces anterior polar follicle cellsJAK-STAT: form the stalk cellsYellow arrow: signals induce E-cadherins expression
The oocyte move towards one end in contact with follicle cellsBoth the oocyte and the posterior follicle cells express high levels of the E-cadherin
If E-cadherin is removed, the oocyte is randomly positioned.Then the oocyte induces surrounding follicle cell to adopt posterior fate.
A/P Determination during oogenesis
The EGFR signal establishes the A/P and D/V axial pattern
Red-actinGreen-gurken proteinAs well as mRNA
The expression of EGFR pathway target gene
Torpedo--EGFR
Specifying the Anterior-Posterior Axis of the
Drosophila Embryo During Oogenesishttp://www.youtube.com/watch?v=GntFBUa6nvs
Specifying the Anterior-Posterior Axis of the
Drosophila Embryo During Oogenesis
Protein kinase A orients the microtubules
mRNA localization in the oocyte
Dynein-gurken and bicoid to the plus endKinesin—oskar to the minus end
The EGFR signal establishes the A/P and D/V axial pattern
Gurken—TGFTorpedo--- EGFR
The localization of Gurken RNA
Cornichon, and Brainiac-Modification and Transportation of the protein
K10, Squid localize gurken mRNA (3’UTR&coding region)
Cappuccino and Spire –cytoskeleton ofthe oocyte
MAPK pathway
The Key determinant in D/V polarity is pipe mRNA in follicle cells
windbeutel—ER protein pipe—heparansulfate 2-o-sulfotransferase (Golgi) nudel—serine protease
The activation of Toll
Perivitelline space
Fig. 31-16
The dorsal-ventral pathway
Maternal genes—Fertilization to cellular blastodermDorsal system—for ventral structure(mesoderm, neurogenic ectoderm)
Toll gene product rescue the defectToll mutant – dorsalized (no ventral structure)
2. Transfer wt cytoplasm into Toll mutant specify a new dorsal-ventral axis (injection site =ventral side) spatzle (ligand) fragment diffuses throughout the space
Toll pathway
Without Toll activationDorsal + cactusToll activation –tube (adaptor) and pelle (kinase)Phosphorylate cactus and promote its degradation
B cell gene expressionDorsal=NF-kBCactus=I-kB
The mechanism of localization of dorsal protein to the nucleus
Dorsalization mutation
The activation of NF-B by TNF-
NLS
Fig. 31-17
The dorsal-ventral pathways
Dorsal nuclear gradientActivates—twist, snail (ventral)Represses—dpp, zen (dorsal)
Fig. 31-19
Toll protein activation results in a gradient of intranuclear dorsal protein
Spatzle is processed in the perivitelline space after fertilization
Fig. 5-8
Zygotic genes pattern the early embryoDorsal protein activates twist and snail represses dpp, zen, tolloid
Rhomboid----neuroectodermRepressed by snail (not most ventral)
Binding sites for dorsal protein in their regulatory regions
Model for the subdivision of the dorso-ventral axis into different regions by the gradient in nuclear dorsal protein
Fig. 5-13
Dorsalized embryo—Dorsal protein is not in nucleiDpp is everywhereTwist and snail are not expressed
Threshold effect—integrating Function of regulatory binding sites
Regulatory element=developmental switches
High affinity (more dorsal region-low conc.)
Low affinity (ventral side-high conc.)
Nuclear gradient in dorsal protein
Fig. 5-14
Dpp protein gradient
Cellularization---signal through transmembrane proteinsDpp=BMP-4(TGF-)Dpp protein levels high, increase dorsal cellsshort of gastrulation (sog) prevent the dpp spreading into neuroectodermSog is degraded by Tolloid (most dorsal)
Snail—(mesoderm)Reduce E-cadherin cell migration
Microarray analysisfor gene expression profile
Smad= Sma + MadSma-C. elegansMad-Fly
1. Antagonist2. Proteases
Fig. 31-24
The TGK-/BMP signaling pathway
dpp: decapentaplegic
Fig. 31-23
The Wnt and BMP pathways are used in early development
The self-renewal signal of the niche-Dpp signaling
EMBO reports, 12, 519-2011
Biological responses to TGF-family signaling
Type I, II receptor-Ser/Thr phosphorylation
The Smad-dependent pathway activated by TGF-
Colorectal cancer: type II receptorPancreatic cancers: 50% Smad
One component between receptor and gene regulation
The Smad-dependent pathway activated by TGF-
De-repression of target genes in Dpp signaling
groucho
Nature reviews genetics-8-663-2007
Activation
repression
Structural and Functional Domains of Smad Family
TGFb , Activin: R-Smad 2,3BMPs: R-Smad 1, 5, 8Common Smad4-nucleocytoplasmic shuttling, DNA bindingInhibitory Smads: I-Smad 6, 7
bioscience.org
Integration of two signal pathways at the
promoter
Cell,95,737, 1998SBE: Smad binding elementARE: activin-response elementTRE: TPA-response element (AP-1 binding)XBE: transcription X
Smad2 and FAST Smad3 and c-Jun/cFos
Overview of TGF-b family signaling
Development, 136-3691-2009
Post-translational modification of TGF- receptor
Trends in Cell Biology, 19, 385-2009
The functions of the TGF- receptors are regulated by protein associations
Trends in Cell Biology, 19, 385-2009
Different internalization pathwaysresulted in distinct cellular effects
Trends in Cell Biology, 19, 385-2009
Models of morphogen gradient formation
Fig. 31-11, 12, 13sharpen
Fig. 31-21
The axis determining systems