Model of Drosophila Anterior-Posterior Pattern Formation

Maternal effect genes

Zygotic genesSyncytial blastoderm

Cellular blastoderm

Homeotic selector genesSimilar signal into different structures—

Different interpretation—controlled by Hox genes

Homeotic transformation of the wing and haltere

Homeotic genes—mutated into homeosis transformationAs positional identity specifiers:Bithorax-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

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+Ubx—5,6+Abd-A—7,8,9+Abd-B—10Combinatorial mannerLack 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)

Regulatory elements

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

Fly and mouse/human genomes of homeotic genes

Expression pattern and the location on chromosome

A/P during oogenesis the oocyte move towards one end in contact with follicle cells. Both 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.

Egg chamber formation

Specifying the Anterior-Posterior Axis of the

Drosophila Embryo During Oogenesis

Specifying the Anterior-Posterior Axis of the

Drosophila Embryo During Oogenesis

Protein kinase A orients the microtubules

Before fertilization ligand immobilized

Small quantities—bound to torso at the poles little left to diffuse

Anterior/posterior extremities

Terminal structure-acron., telson, most posterior abdominal segment

Torso---receptor tyrosine kinaseLigand---trunk

Torso signaling

Groucho: repressorHuckenbein, tailless are released from transcriptional suppression

The EGFR signal establishes the A/P and D/V axial pattern

Gurken—TGFTorpedo--- EGFR

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

The localization of Gurken RNA

Cornichon, and brainiac-Modification and Transportation of the protein

K10, squid localize gurken mRNA

Cappuccino and spire –cytoskeleton ofthe oocyte

The Key determinant in D/V polarity is pipe mRNA in follicle cells

Cross section

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-

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 periviteline space after fertilization

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

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

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)

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

Signal Pathways Induced by Cellular Surface Receptors

Mol. Cell. Biol. 5th ed. 2004, Lodish et al.

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

Nature reviews genetics-8-663-2007

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

Cell, 95,737,1998

13,216, 2003

NLS , NES

Smad4 shuttles between the cytosol and nucleus

Inhibitory Smads: I-Smad 6, 7

—recruting Smurf (ubiquitin ligase to receptor)

Cell, 95,737,1998

2005, 17:107

Different internalization pathwaysresulted in distinct cellular effects

Models of morphogen gradient formation

Fig. 31-11, 12, 13sharpen

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

Fig. 31-21

The axis determining systems