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Regulation of Gene Expression Chapter 18
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Gene expression Flow of genetic information Genotype to phenotype Genes to proteins Proteins not made at random Specific purposes Appropriate times
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Control of gene expression Selective expression of genes All genes are not expressed at the same time Expressed at different times
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Prokaryote regulation
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Control of gene expression Regulate at transcription Gene expression responds to Environmental conditions Type of nutrients Amounts of nutrients Rapid turn over of proteins
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Fig. 18-2 Regulation of gene expression trpE gene trpD gene trpC gene trpB gene trpA gene (b) Regulation of enzyme production (a) Regulation of enzyme activity Enzyme 1 Enzyme 2 Enzyme 3 Tryptophan Precursor Feedback inhibition
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Prokaryote Anabolism: Building up of a substance Catabolism: Breaking apart a substance
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Prokaryote Operon Section of DNA Enzyme-coding genes Promoter Operator Sequence of nucleotides Overlaps promoter site Controls RNA polymerase access to the promoter
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Figure 18.3a Promoter DNA trpR Regulatory gene RNA polymerase mRNA 5′5′ 3′3′ Protein Inactive repressor mRNA 5′ (a) Tryptophan absent, repressor inactive, operon on Promoter trp operon Genes of operon trpE trpDtrpCtrpBtrpA Operator Start codon Stop codon Polypeptide subunits that make up enzymes for tryptophan synthesis EDCB A
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Prokaryote Multiple genes are expressed in a single gene expression trp operon – Trytophan – Synthesis Lac operon – Lactose – Degradation
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Prokaryote trp Operon: Control system to make tryptophan Several genes that make tryptophan Regulatory region
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Fig. 18-3a Polypeptide subunits that make up enzymes for tryptophan synthesis mRNA 5 RNA polymerase Promoter trp operon Genes of operon Operator Stop codon Start codon mRNA trpA 5 trpE trpD trpCtrpB AB CD E
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Prokaryote ⇧ tryptophan present Bacteria will not make tryptophan Genes are not transcribed Enzymes will not be made Repression
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Prokaryote Repressors Proteins Bind regulatory sites (operator) Prevent RNA polymerase attaching to promoter Prevent or decrease the initiation of transcription
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Prokaryote Repressors Allosteric proteins Changes shape Active or inactive
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Prokaryote ⇧ tryptophan Tryptophan binds the trp repressor Repressor changes shape Active shape Repressor fits DNA better Stops transcription Tryptophan is a corepressor
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Fig. 18-3b-2 (b) Tryptophan present, repressor active, operon off Tryptophan (corepressor) No RNA made Active repressor mRNA Protein DNA
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Prokaryote ⇩ tryptophan Nothing binds the repressor Inactive shape RNA polymerase can transcribe
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Fig. 18-3a Polypeptide subunits that make up enzymes for tryptophan synthesis (a) Tryptophan absent, repressor inactive, operon on DNA mRNA 5 ProteinInactive repressor RNA polymerase Regulatory gene Promoter trp operon Genes of operon Operator Stop codon Start codon mRNA trpA 5 3 trpRtrpE trpD trpCtrpB AB CD E
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Prokaryote Lactose Sugar used for energy Enzymes needed to break it down Lactose present Enzymes are synthesized Induced
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Prokaryote lac Operon Promoter Operator Genes to code for enzymes Metabolize (break down) lactose
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Prokaryote Lactose is present Repressor released Genes expressed Lactose absent Repressor binds DNA Stops transcription
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Prokaryote Allolactose: Binds repressor Repressor releases from DNA Inducer Transcription begins Lactose levels fall Allolactose released from repressor Repressor binds DNA blocks transcription
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Fig. 18-4b (b) Lactose present, repressor inactive, operon on mRNA Protein DNA mRNA 5 Inactive repressor Allolactose (inducer) 5 3 RNA polymerase Permease Transacetylase lac operon -Galactosidase lacY lacZlacAlac I
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Fig. 18-4a (a) Lactose absent, repressor active, operon off DNA Protein Active repressor RNA polymerase Regulatory gene Promoter Operator mRNA 5 3 No RNA made lac I lacZ
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Prokaryote Lactose & tryptophan metabolism Adjustment by bacteria Regulates protein synthesis Response to environment Negative control of genes Operons turned off by active repressors Tryptophan repressible operon Lactose inducible operon
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Prokaryote
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Activators: Bind DNA Stimulate transcription Involved in glucose metabolism lac operon
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Prokaryote Activator: Catabolite activator protein (CAP) Stimulates transcription of operons Code for enzymes to metabolize sugars cAMP helps CAP cAMP binds CAP to activate it CAP binds to DNA (lac Operon)
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Prokaryote Glucose elevated cAMP low cAMP not available to bind CAP Does not stimulate transcription Bacteria use glucose Preferred sugar over others.
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Prokaryote lac operon Regulated by positive & negative control Low lactose Repressor blocks transcription High lactose Allolactose binds repressor Transcription happens
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Prokaryote lac operon Glucose also present CAP unable to bind Transcription will proceed slowly Glucose absent CAP binds promoter Transcription goes quickly
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Figure 18.5 Promoter DNA Operator Promoter DNA CAP-binding site cAMP Active CAP Inactive CAP RNA polymerase binds and transcribes lac I I Allolactose Inactive lac repressor (a) Lactose present, glucose scarce (cAMP level high): abundant lac mRNA synthesized lacZ CAP-binding site RNA polymerase less likely to bind Operator Inactive CAP Inactive lac repressor (b) Lactose present, glucose present (cAMP level low): little lac mRNA synthesized
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Eukaryote gene expression All cells in an organism have the same genes Some genes turned on Others remain off Leads to development of specialized cells Cellular differentiation
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Eukaryote gene expression Gene expression assists in regulating development Homeostasis Changes in gene expression in one cell helps entire organism
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Control of gene expression Chromosome structure Transcriptional control Posttranscriptional control
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Fig. 18-6 DNA Signal Gene NUCLEUS Chromatin modification Chromatin Gene available for transcription Exon Intron Tail RNA Cap RNA processing Primary transcript mRNA in nucleus Transport to cytoplasm mRNA in cytoplasm Translatio n CYTOPLASM Degradation of mRNA Protein processing Polypeptide Active protein Cellular function Transport to cellular destination Degradation of protein Transcription
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Eukaryotes 1. DNA is organized into chromatin 2. Transcription occurs in nucleus 3. Each gene has its own promoter
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Chromatin structure DNA is tightly packaged Heterochromatin: Tightly packed Euchromatin: Less tightly packed Influences gene expression Promoter location Modification of histones
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Chromatin structure Histone acetylation Acetyl groups (-COCH 3 ) Attach to Lysines in histone tails Loosen packing Histone methylation Methyl groups (-CH 3 ) Tightens packing
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Fig. 18-7 Histone tails DNA double helix (a) Histone tails protrude outward from a nucleosome Acetylated histones Amino acids available for chemical modification (b) Acetylation of histone tails promotes loose chromatin structure that permits transcription Unacetylated histones
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Chromatin structure Methylation of bases (cytosine) Represses transcription Embryo development
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Eukaryotes Epigenetic change: Chromatin modifications Change in gene expression Passed on to the next generation Not a DNA sequence change
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Transcription control RNA polymerase must bind DNA Proteins regulate by binding DNA RNA polymerase able to bind or not Stimulates transcription or blocks it
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Fig. 18-8-3 Enhancer (distal control elements) Proximal control elements Poly-A signal sequence Termination region Downstream Promoter Upstream DNA Exon Intron Exon Intron Cleaved 3 end of primary transcript Primary RNA transcript Poly-A signal Transcription 5 RNA processing Intron RNA Coding segment mRNA 5 Cap 5 UTR Start codon Stop codon 3 UTR Poly-A tail 3
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Eukaryotes Transcription RNA Polymerase Transcription factors (regulatory proteins) General transcription factors (initiation complex) Specific transcription factors
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Eukaryotes Initiation of transcription Activator proteins Activator binds the enhancers Enhancers (DNA sequences) Interacts with the transcription factors Binds to the promoter RNA polymerase binds and transcription begins
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Fig. 18-9-2 Enhancer TATA box Promoter Activators DNA Gene Distal control element Group of mediator proteins DNA-bending protein General transcription factors
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Fig. 18-9-3 Enhancer TATA box Promoter Activators DNA Gene Distal control element Group of mediator proteins DNA-bending protein General transcription factors RNA polymerase II RNA polymerase II Transcription initiation complex RNA synthesis
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Eukaryotes
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Fig. 18-10 Control elements Enhancer Available activators Albumin gene (b) Lens cell Crystallin gene expressed Available activators LENS CELL NUCLEUS LIVER CELL NUCLEUS Crystallin gene Promoter (a) Liver cell Crystallin gene not expressed Albumin gene expressed Albumin gene not expressed
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Post transcriptional control RNA processing Primary transcript: Exact copy of the entire gene RNA splicing Introns removed from the mRNA snRNP’s (small nuclear ribonulceoproteins)
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Post transcriptional control Splicing plays a role in gene expression Exons can be spliced together in different ways. Leads to different polypeptides Originated from same gene
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Post transcriptional control Example in humans Calcitonin & CGRP Hormones released from different organs Derived from the same transcript
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Fig. 18-11 or RNA splicing mRNA Primary RNA transcript Troponin T gene Exons DNA
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Post transcriptional control
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Transport of transcript Passes through nuclear pores Active transport Cannot pass until all splicing is done
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Post transcriptional control mRNA degradation Life span Some can last hours, a few weeks mRNA for hemoglobin survive awhile
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Post transcriptional control
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Translation of RNA Translation factors are necessary Regulate translation Translation repressor proteins Stop translation Bind transcript Prevents it from binding to the ribosome
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Post transcriptional control
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Ferritin (iron storage) Aconitase: Translation repressor protein Binds ferritin mRNA Iron will bind to aconitase Aconitase releases the mRNA Ferritin production increases Post transcriptional control
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Protein modification Phosphorylation Other alterations can affect the activity of protein Insulin Starts out as a larger molecule Cut into more active sections
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Post transcriptional control Protein modification Degradation Protein is marked by small protein Protein complex then breaks down proteins Proteasomes
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Post transcriptional control
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Fig. 18-UN4 Genes in highly compacted chromatin are generally not transcribed. Chromatin modification DNA methylation generally reduces transcription. Histone acetylation seems to loosen chromatin structure, enhancing transcription. Chromatin modification Transcription RNA processing Translation mRNA degradation Protein processing and degradation mRNA degradation Each mRNA has a characteristic life span, determined in part by sequences in the 5 and 3 UTRs. Protein processing and degradation by proteasomes are subject to regulation. Protein processing and degradation Initiation of translation can be controlled via regulation of initiation factors. Translation ormRNA Primary RNA transcript Alternative RNA splicing: RNA processing Coordinate regulation: Enhancer for liver-specific genes Enhancer for lens-specific genes Bending of the DNA enables activators to contact proteins at the promoter, initiating transcription. Transcription Regulation of transcription initiation: DNA control elements bind specific transcription factors.
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Post transcriptional control Most gene regulation-transcription New discovery Small RNA’s 21-28 nucleotides long Play a role in gene expression New transcript before leaving the nucleus
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RNA interference RNA forming double stranded loops from newly formed mRNA Loops are formed Halves have complementary sequences Loops inhibit expression of genes Where double RNA came from Post transcriptional control
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Dicer: Cuts double stranded RNA into smaller RNA’s called microRNA (miRNA) Small interfering RNA (siRNA’s)
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Fig. 18-13 miRNA- protein complex (a) Primary miRNA transcript Translation blocked Hydrogen bond (b) Generation and function of miRNAs Hairpin miRNA Dicer 3 mRNA degraded 5
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Post transcriptional control miRNA’s bind mRNA Prevents translation siRNA’s breaks apart mRNA before it’s translated
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Post transcriptional control siRNAs play a role in heterochromatin formation Block large regions of the chromosome Small RNAs may also block transcription of specific genes
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Fig. 18-UN5 Chromatin modification RNA processing Translation mRNA degradation Protein processing and degradation mRNA degradation miRNA or siRNA can target specific mRNAs for destruction. miRNA or siRNA can block the translation of specific mRNAs. Transcription Small RNAs can promote the formation of heterochromatin in certain regions, blocking transcription. Chromatin modification Translation
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Embryonic development Zygote gives rise to many different cell types Cells → tissues → organs → organ systems Gene expression Orchestrates developmental programs of animals
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Fig. 18-14a (a) Fertilized eggs of a frog
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Embryonic development Zygote to adult results Cell division Cell differentiation: Cells become specialized in structure & function Morphogenesis: “creation of from” Body arrangement
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Fig. 47-6 (a) Fertilized egg(b) Four-cell stage(c) Early blastula(d) Later blastula
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Fig. 47-1 1 mm
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Fig. 46-17 (a) 5 weeks (b) 14 weeks (c) 20 weeks
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Embryonic development All cells same genome Differential gene expression Genes regulated differently in each cell type
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Fig. 18-10 Control elements Enhancer Available activators Albumin gene (b) Lens cell Crystallin gene expressed Available activators LENS CELL NUCLEUS LIVER CELL NUCLEUS Crystallin gene Promoter (a) Liver cell Crystallin gene not expressed Albumin gene expressed Albumin gene not expressed
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Embryonic development Specific activators Materials in egg cytoplasm Not homogeneous Set up gene regulation Carried out as cells divide
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Embryonic development Cytoplasmic determinants Maternal substances in the egg Influence early development Zygote divides by mitosis Cells contain different cytoplasmic determinants Leads to different gene expression
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Fig. 18-15a (a) Cytoplasmic determinants in the egg Two different cytoplasmic determinants Unfertilized egg cell Sperm Fertilization Zygote Mitotic cell division Two-celled embryo Nucleus
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Embryonic development Environment around cell influences development Induction: Signals from nearby embryonic cells Cause transcriptional changes in target cells Interactions between cells induce differentiation of specialized cell types
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Fig. 18-15b (b) Induction by nearby cells Signal molecule (inducer) Signal transduction pathway Early embryo (32 cells) NUCLEUS Signal receptor
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Embryonic development Determination: Observable differentiation of a cell Commits a cell to its final fate Cell differentiation is marked by the production of tissue-specific proteins Gives cell characteristic structure & function
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Embryonic development Myoblasts: Produce muscle-specific proteins Form skeletal muscle cells MyoD One of several “master regulatory genes” Produces proteins Commit cells to becoming skeletal muscle
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Embryonic development MyoD protein Transcription factor Binds to enhancers of various target genes Causes expression
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Fig. 18-16-1 Embryonic precursor cell Nucleus OFF DNA Master regulatory gene myoD Other muscle-specific genes OFF
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Fig. 18-16-2 Embryonic precursor cell Nucleus OFF DNA Master regulatory gene myoD Other muscle-specific genes OFF mRNA MyoD protein (transcription factor) Myoblast (determined)
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Fig. 18-16-3 Embryonic precursor cell Nucleus OFF DNA Master regulatory gene myoD Other muscle-specific genes OFF mRNA MyoD protein (transcription factor) Myoblast (determined) mRNA Myosin, other muscle proteins, and cell cycle– blocking proteins Part of a muscle fiber (fully differentiated cell) MyoD Another transcription factor
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Embryonic development Pattern formation: Development of spatial organization of tissues & organs Begins with establishment of the major axes Positional information: Molecular cues control pattern formation Tells a cell its location relative to the body axes & neighboring cells
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Figure 18.24 G protein Growth factor Receptor Protein kinases Transcription factor (activator) NUCLEUS Protein that stimulates the cell cycle Transcription factor (activator) NUCLEUS Overexpression of protein Ras MUTATION GTP Ras protein active with or without growth factor. PP PP PP 1 3 2 5 4 6
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Figure 18.25 Protein kinases DNA damage in genome Active form of p53 Transcription DNA damage in genome UV light Defective or missing transcription factor. Inhibitory protein absent Protein that inhibits the cell cycle NUCLEUS MUTATION 1 34 2 5
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Fruit fly Unfertilized egg contains cytoplasmic determinants Determines the axes before fertilization After fertilization, Embryo develops into a segmented larva with three larval stages
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Fig. 18-17a Thorax HeadAbdomen 0.5 mm Dorsal Ventral Right Posterior Left Anterior BODY AXES (a) Adult
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Fig. 18-17b Follicle cell Nucleus Egg cell Nurse cell Egg cell developing within ovarian follicle Unfertilized egg Fertilized egg Depleted nurse cells Egg shell Fertilization Laying of egg Body segments Embryonic development Hatching 0.1 mm Segmented embryo Larval stage (b) Development from egg to larva 1 2 3 4 5
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Fruit fly Homeotic genes: Control pattern formation in late embryo,larva and adult
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Fig. 18-18 Antenna Mutant Wild type Eye Leg
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Fruit fly Maternal effect genes: Encode for cytoplasmic determinants Initially establish the axes of the body of Drosophila Egg-polarity genes: Maternal effect genes Control orientation of the egg Consequently the fly
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Fruit Fly Bicoid gene Maternal effect gene Affects the front half of the body An embryo whose mother has a mutant bicoid gene Lacks the front half of its body Duplicate posterior structures at both ends
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Fig. 18-19a T1T2 T3 A1 A2 A3A4 A5 A6 A7 A8 A7 A6 A7 Tail Head Wild-type larva Mutant larva (bicoid) EXPERIMENT A8
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