Genetics: From Genes to Genomes

Genetics: From Genes to Genomes
PowerPoint to accompany Genetics: From Genes to Genomes Fourth Edition Leland H. Hartwell, Leroy Hood, Michael L. Goldberg, Ann E. Reynolds, and Lee M. Silver Prepared by Mary A. Bedell University of Georgia Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition

18 Using Genetics to Study Development CHAPTER OUTLINE PART V
How Genes Are Regulated CHAPTER Using Genetics to Study Development CHAPTER OUTLINE 18.1 Model Organisms: Prototypes for Developmental Genetics 18.2 Using Mutations to Dissect Development 18.3 Analysis of Developmental Pathways 18.4 A Comprehensive Example: Body-Plan Development in Drosophila 18.5 How Genes Help Control Development Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 18

How does the single cell of a fertilized egg differentiate into thousands of cell types?
Figure 18.1 Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 18

Model organisms: Prototypes for developmental genetics
Five model organisms: Saccharomyces cerevisiae (yeast) Arabidopsis thaliana (plant) Drosophila melanogaster (fruit fly) Caenorhabditis elegans (roundworm) Mus musculus (mouse) Advantages for research Easy to grow Rapid reproduction Genetic resources e.g. stock centers that maintain and share mutant strains Genome sequencing Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 18

Two of the model organisms used in developmental genetics
Mutations in Drosophila genes can affect early embryonic development Transparency of C. elegans facilitates study of the worm’s development Figure 18.3 Figure 18.2 Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 18

All living forms are related
Cells of many eukaryotes have microscopic features in common – e.g. nuclei and mitochondria Metabolic pathways are virtually identical in all organisms Almost all cells use the same genetic code Many homologous proteins have highly conserved amino acid sequences Many developmental strategies are conserved in multicellular eukaryotes Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 18

A transcription factor that is critical for eye development in Drosophila and mouse
Drosophila with mutant alleles of the eyeless gene Mouse embryos with wild-type (L) and mutant (R) alleles of the Pax-6 gene Figure 18.4b Humans with mutations in the Pax-6 gene have aniridia (not shown) Figure 18.4a Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 18

Despite many biological similarities, all species are unique
Disparate strategies are used by different organisms to accomplish the same developmental goal Example: cell fate differences in two-cell embryos of C. elegans and humans Mosaic determination in C. elegans Each cell has been assigned a developmental fate Abnormal development if one cell is removed Regulative determination in humans Cells can alter their development fates according to the environment Twins result if the two cells are separated Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 18

Using mutations to dissect development
Identification of different alleles of the same gene can be important to understanding developmental processes Loss-of-function mutations - usually recessive Can alter the amino acid sequence – results in diminished (or no) biochemical activity Can interfere with gene expression (transcription, RNA processing, translation) – results in decreased (or no) expression of a normal protein Gain-of function mutations – usually dominant Can produce too much protein, or proteins with new function Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 18

Loss-of-function mutations that are recessive
Null mutations – complete loss-of-function Knockouts can be made by gene-targeting (Fig 18.5) Hypomorphic mutations – partial loss-of-function Useful for understanding how one gene functions at multiple times in development e.g. wingless gene in Drosophila is essential for viability of embryos and for formation of wings in adults Conditional mutations – loss-of-function only under certain conditions e.g. Temperature-sensitive mutations (Fig 18.6) Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 18

Constructing knockout mice: Creating a cell line with a knockout allele of a gene
Use recombinant DNA techniques to insert the neomycin (neo) resistance gene into the gene of interest Embryonic stem (ES) cell line established from early embryos of agouti mice Introduce disrupted gene into ES cells and select for neomycin resistance Identify ES colony with knockout allele Figure 18.5a -c Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 18

Constructing knockout mice: Creating mice that carry the knockout gene
Produce blastocysts by breeding black mice Inject targeted ES cells into blastocysts and put blastocysts into uterus of another black mouse Offspring will be chimeric and can transmit knockout allele to their offspring Figure 18.5d - f Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 18

Time-of-function analysis using a temperature-sensitive mutation
Embryonic development in C. elegans females homozygous for zyg-9 gene At permissive temperature, development is normal After short pulse of higher temperature, development is normal during some windows of time and abnormal during a critical period of time Figure 18.6 Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 18

Loss-of-function mutations that are dominant
Haploinsufficiency In some genes, one wild-type allele is not sufficient for normal development Dominant negative mutations Inactive protein expressed from mutant allele reduces the function of normal protein expressed from the wild- type allele Example: multimeric proteins (Fig 8.31 on p. 279), or mutant receptor that sequesters a ligand (Fig 18.7) Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 18

Engineering a dominant-negative mutation in fibroblast growth factor receptor (FGFR)
Figure 18.7 Normal FGFR is on the cell surface and interacts with extracellular ligand Mutant FGFR cannot localize to cell surface Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 18

Phenotypic effects of dominant-negative FGFR
Transgenic mice expressing mutant FGFR had several defects, including abnormal limb development Non-transgenic mouse limb Transgenic mouse limb Figure 18.7c Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 18

RNA interference (RNAi) disrupts gene function without mutations
RNAi targets the degradation of mRNA from specific genes Vector constructed to synthesize double-stranded (ds) RNA with sequence to gene of interest (Fig 18.8a) dsRNA introduced into developing embryos dsRNA is degraded into shorter fragments that serve as templates for degradation of target mRNAs Can produce a phenocopy of a loss-of-function mutation Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 18

Synthesis of dsRNA and abnormal development caused by RNAi in C
Synthesis of dsRNA and abnormal development caused by RNAi in C. elegans Wild-type vulva, no dsRNA Abnormal vulva, dsRNA for par-1 Figure 18.8 Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 18

Gain-of-function mutations are usually dominant
Mutations causing excessive gene activity Results from highly specific alterations Much less frequent than loss-of-function mutations Several mechanisms: promoter mutations that increase transcription, mutations in receptors that increase affinity for ligand, mutations in receptors that cause constitutive activity Mutations causing ectopic gene expression Expression of a gene in an abnormal place or time Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 18

Achondroplastic dwarfism in the mouse is caused by constitutive activation of FGFR3

Ectopic expression of the eyeless gene produces ectopic eye tissue in Drosophila
Transgenic flies with eyeless gene under control of a heat- shock promoter Flies grown at high temperature have high eyeless expression in all parts of the body Ectopic eye development in different parts of body Figure 18.10 Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 18

Analysis of developmental pathways
Characterize the action of each gene in a pathway Nature of the encoded protein Infer amino acid sequence from nucleotide sequence Computer searches to identify known motifs Location and timing of gene expression During development, where and when is the mRNA found? Location of the protein product During development, where and when is the protein found? Developmental phenotypes What cells or tissues are affected by loss-of-function? Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 18

A motif found in many transcription factors that regulate development
Homeodomain – DNA binding domain Interacts with specific sequences in DNA Figure 18.11 Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 18

In situ hybridization locates cells expressing a gene of interest
Labeled cDNA for Pax-6 gene used as a probe on sections of human fetal tissues Hybridization of Pax-6 probe to the developing neural retina and eye lens Figure 18.12 Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 18

Using antibody tagging to follow the localization of proteins
Synthetic gene encodes a fusion protein, which can be expressed in bacteria and then used to generate specific antibodies Staining of Drosophila imaginal disc with fluorescently-labeled antibodies against several proteins Figure 18.13a, b Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 18

Using GFP tagging to follow the localization of proteins
Recombinant gene encoding a fusion protein with green fluorescent protein (GFP) at the C terminus A mouse with a GFP-tagged transgene expressed in the skin Figure 18.13c, d Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 18

Using genetic mosaics to understand developmental phenotypes in Arabidopsis
Blue tissue has a marker gene and is AGAMOUS+ White tissue doesn't have the marker gene and is AGAMOUS− Signal from blue AGAMOUS+ L2 cell is needed for proper differentiation of L1 cells Figure 18.14 Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 18

Interactions of genes in a developmental pathway must be determined
Genes don't work in isolation! Many biological processes are complicated and require coordinated action of many genes Analysis of effects of one gene on expression of another gene Does a mutation in one gene affect the level or distribution of mRNA or protein from another gene? Analysis of double mutants – epistatic interactions Do mutations in two different genes define successive steps in a pathway? Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 18

In Drosophila, the wingless gene product is required for expression of the vestigial gene
Staining of Drosophila wing imaginal disks for wingless protein (Wg, green) and vestigial protein (Vg, red) (top) Wild-type Yellow is observed in cells expressing both Wg and Vg (bottom) wingless mutant Vg protein appears only in a very narrow band Figure 18.15 Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 18

Genetic interactions that can be defined by analysis of double mutants
Epistasis – usually defines the earlier acting step in the pathway Phenotype of double mutant resembles one of the single mutants Suppressor – mutation in one gene counteracts the effects of mutation in another gene Phenotype of double mutant is similar to wild-type Enhancer – mutation in one gene exacerbates the effects of mutation in another gene Phenotype of double mutant is worse than either single mutant Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 18

Double mutant analysis: Epistasis in the secretion pathway
Mutant for both gene A and gene B has phenotype like that of mutant for gene A only Both proteins act in the same pathway Gene A protein acts earlier than gene B − gene A is epistatic to gene B Figure 18.16a Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 18

Double mutant analysis: Epistasis in the pathway for vulva formation
In this case, MEK-2 acts at a later step in the pathway than LET-60 But, a mutation in MEK-2 is epistatic to a mutation in LET-60 Figure 18.16b Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 18

Interpreting the results of double mutant analysis
Is the effect due to epistasis, a suppressor, or an enhancer? Need more information in addition to double mutant phenotype: Are the mutations loss-of-function or gain-of-function? Does the whole pathway have a single output or does blocking different steps have a different outcome? What are the biochemical roles (e.g. transcription factor, kinase, hormone receptor) of the encoded proteins? Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 18

A comprehensive example: Genetic analysis of body-plan development in Drosophila
Clearly defined segments are formed in the embryo and each segment forms a specific structure in the adult How does the developing embryo establish the proper number of body segments? Early in development, the products of segmentation genes subdivide the body into an array of identical body segments How does each body segment know what kind of structures it should form? Later in development, the products of homeotic genes assign a unique identity to each segment Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 18

Early Drosophila development: From fertilization to cellular blastoderm
During the first three hours after fertilization: Syncytial blastoderm formed by 13 very rapid mitotic divisions without any cell division Cellular blastoderm formed by cellularization that begins during interphase of 14th division Figure 18.17a Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 18

Drosophila development after formation of the cellular blastoderm
Gastrulation begins immediately after cellularization Furrows lead to establishment of three embryonic germ layers: mesoderm, ectoderm, endoderm First visible signs of segmentation appear 40 min after gastrulation begins By 10 hrs after fertilization, 14 body segments are formed Figure 18.18a - c Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 18

Segment identity is preserved throughout Drosophila development
Each embryonic segment defines a specific structure in the adult 3 head segments 3 thoracic segments 6 abdominal segments Figure 18.18d Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 18

Genetic screens for mutations affecting early development of Drosophila embryos
Christiane Nusslein-Vollhard and Eric Wieschaus (both shared the Nobel Prize with Edward Lewis in 1995) Two mutagenesis screens to identify genes that control embryonic development: 1. Screened for abnormal embryos in homozygous mutant females Identified recessive mutations in maternal-effect genes 2. Screened for abnormal homozygous mutant embryos Identified recessive mutations in three classes of zygotic segmentation genes Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 18

Four classes of genes responsible for segment formation in Drosophila embryos
Function in a hierarchy that progressively subdivides the embryo into successively smaller units Maternal genes – expressed by mother and the mRNAs deposited in egg, not translated until after fertilization Gap genes – expression begins at syncytial blastoderm stage and controlled by maternal gene products Pair-rule genes – seven zones of expression are controlled by gap gene products Segment polarity genes – expression in 14 segments is controlled by pair-rule gene products Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 18

Two morphogens control anterior and posterior patterning in the Drosophila embryo
Morphogen – substance that defines different cell fates in a concentration-dependent manner Two maternal-effect gene products [bicoid (bcd) and nanos (nos)] are morphogens bcd and nos genes are transcribed by the mother and their mRNAs are localized to opposite poles of the oocyte bcd and nos mRNAs are not translated in the embryo until after fertilization Each protein forms a gradient in the embryos: bcd is highest at anterior and lowest at the posterior nos is lowest at anterior and highest at posterior Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 18

Localization of bicoid mRNA and protein
bcd mRNA localizes to the anterior pole of the oocyte bcd protein diffuses from the anterior pole of the embryo to produce an anterior-to-posterior gradient bcd protein acts as transcription factor and translation repressor Figure 18.19a, b Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 18

Evidence that bicoid is the anterior morphogen
Dosage of maternal bcd gene determines how much of the embryo becomes head structures Figure 18.19c Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 18

Distribution of mRNAs of the four maternal-effect genes within oocytes
Bicoid (bcd) mRNA localizes to anterior pole Nanos (nos) mRNA localizes to the posterior pole Hunchback (hb) and caudal (cad) mRNAs are uniformly distributed Figure 18.20 Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 18

Distribution of the protein products of maternal-effect genes within the early embryo
Bicoid protein represses translation of caudal mRNA Causes posterior-to-anterior gradient of caudal protein Nanos protein represses translation of hunchback mRNA Causes anterior-to-posterior gradient of hunchback protein Figure 18.20 Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 18

Segment number is further specified by zygotic genes
Bicoid, hunchback, and caudal proteins are transcription factors that control the spatial expression of zygotic genes Zygotic gene expression begins in the syncytial blastoderm stage Three classes of zygotic segmentation genes: 9 gap genes 8 pair-rule genes 17 segment polarity genes Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 18

Zones of gap gene expression
Gap genes (Krüppel, hunchback, knirps, and giant) are the first zygotic genes expressed Binding sites in promoter regions of gap genes have different affinities for bcd, cad, and hb proteins Some gap genes encode transcription factors that control expression of other gap genes Gap gene products control division of the body axis into rough, generalized regions Figure 18.21a Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 18

Embryos with segmentation defects caused by mutations in gap genes
normal hunchback Krüppel knirps Figure 18.21b Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 18

Mutation of a particular gap gene results in loss of segments corresponding to its zone of expression Figure 18.21c Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 18

Two classes of pair-rule genes
Three primary pair-rule genes Expression is controlled by transcription factors encoded by maternal genes and zygotic gap genes Upstream region of each pair-rule gene has multiple binding sites for transcription activation/repression Five secondary pair-rule genes Expression is controlled by transcription factors encoded by other pair-rule genes Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 18

Pair-rule genes are expressed in seven stripes at the early blastoderm stage
e.g. even-skipped (eve) and fushi tarazu (ftz) Expression of pair-rule genes divides the body axis into sharply-defined stripes Two-segment periodicity: each stripe has two segments In stripe 2, eve transcription is activated by Bcd and Hb, but repressed by giant (Gt) and Krüppel (Kr) proteins Figure 18.22a, b Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 18

Upstream regulatory region of the eve gene
700 bp region contains multiple binding sites for Krüppel (Kr), giant (Gt), bicoid (Bcd) and hunchback (Hb) proteins Binding of Kr and Gt proteins represses eve transcription Binding of Bcd and Hb proteins activates eve transcription Figure 18.22c Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 18

Segment polarity genes determine patterns that are repeated in each segment
e.g. Engrailed (en), hedgehog (hh), and wingless (wg) Activation occurs after cellularization – diffusion of proteins within the syncytium no longer plays a role in patterning Intrasegmental patterning is determined primarily by diffusion of secreted factors (e.g. Hh and Wg) between cells Transcription factors encoded by pair-rule genes initiate expression of segment polarity genes in each segment Interactions between various polarity genes maintains the periodicity Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 18

Distribution of engrailed protein in 14 stripes
Segment polarity genes are expressed in stripes that are repeated with single segment periodicity (one stripe per segment) Figure 18.23a Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 18

En, Hh, and Wg are responsible for many aspects of segmental patterning
En protein is a transcription factor Hh and Wg proteins are morphogens that bind to specific receptors on cells in adjacent segments Activate signal transduction pathways that contain proteins encoded by other segment polarity genes En activates transcription of the hh gene in the posterior compartment Hh protein initiates a signal that results in activation of wg transcription in the adjacent anterior compartment Wg protein initiates a signal that results in activation of en and hh transcription in the adjacent posterior compartment Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 18

Segment polarity genes establish compartment borders
Signal transduction pathways initiated by Hh and Wg result in a reciprocal loop that stabilizes cell fates at the borders of adjacent segments Figure 18.23b Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 18

The genetic hierarchy leading to segmentation in Drosophila
In successive levels of the hierarchy, genes are expressed in narrower bands Figure 18.24a Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 18

Mutations in segmentation genes cause segment loss
These mutant embryos have lost part of each segment Often, the remaining part of the segment will be a mirror- image duplication Figure 18.24b Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 18

Segment identity is established by homeotic genes
Transcription of homeotic genes is controlled by gap, pair- rule, and segmentation genes At the cellular blastoderm stage, each homeotic gene is expressed within a subset of body segments Homeotic genes are master regulators that control transcription of many genes responsible for development of segment-specific structures Homeotic mutations cause particular segments to develop as if they were located elsewhere in the body Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 18

Bithorax (bx) and postbithorax (pbx) mutants have homeotic transformations in the third thoracic segment (T3) Wild type bx mutant pbx mutant bx pbx double mutant Figure 18.25 bx mutant: anterior T3 transformed into anterior T2 pbx mutant: posterior T3 transformed into posterior T2 Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 18

Two clusters of homeotic selector genes control most aspects of segment identity
Both clusters of genes are on chromosome 3 Genes in Antennapedia complex (ANT-C) control segments in the head and anterior thorax Genes in bithorax complex (BX-C) control segments in the abdomen and posterior thorax Figure 18.26 Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 18

The bithorax complex of Drosophila
Three BX-C genes: Ultrabithorax (Ubx) abdominal-A (abd-A) Abdominal-B (Abd-B) Figure 18.27 Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 18

The BX-C has multiple regulatory regions that control expression of three genes
Edward Lewis (shared Nobel Prize in 1995 with Nusslein- Vollhard and Wieschaus) Identified infra-abdominal (iab) mutations – mutations in the BX-C that affect each of the abdominal segments Many of the bx, pbx, and iab mutations affect large cis- regulatory regions that control spatial and temporal expression of Ubx, abdA, and AbdB Order of regulatory regions corresponds to the anterior-to- posterior order of segments Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 18

The Antennapedia complex of Drosophila
ANT-C complex controls segment identities in the head and anterior thorax Five genes: labial (lab) – expressed in intercalary regions proboscipedia (pb) – expressed in maxillary and labial segments Deformed (Dfd) – expressed in the mandibular and maxillary segments Sex combs reduced (Sxr) – expressed in labial and T1 segments Antennapedia (Antp) – expressed mainly in T2 Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 18

The homeodomain in development and evolution
Homeobox – a 180 bp region of closely-related sequence found in homeotic genes (at ANT-C and BX-C), as well as some non-homeotic genes (bicoid and eyeless) Encodes a 60 amino acid homeodomain, which is a DNA binding domain Hox gene clusters found in all animal genomes More Hox genes are found in animals with a more complex body plan Humans and other mammals have 38 Hox genes that are in four clusters (see Fig 18.28) In all organisms, linear order of genes in each cluster reflect their anterior-to-posterior expression Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 18

The mammalian Hox genes are organized into four clusters

Synpolydactyly caused by mutations in the human HoxD13 gene

Development requires sequential changes in gene expression
Different cell types express characteristic subsets of genes Cell fate is progressively refined Once a developmental fate is determined, the cell and its descendants follow a differentiation path that excludes an alternative fate Transcriptional regulation plays a key role Posttranscriptional gene regulation also is important e.g. splicing, transport to nucleus, mRNA stability, translational regulation, protein stability Earliest stages of development require both maternal and zygotic gene products Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 18

Development requires precise control of the expression of many genes
Wing imaginal discs of Drosophila Each disk was stained with a fluorescent antibody against a different protein Figure 18.31 Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 18

Development exploits asymmetries
Cells must be exposed to different environmental signals or they must be intrinsically distinct at the biochemical level In some species, the egg is inherently asymmetrical Drosophila egg has an anterior-to-posterior polarity because of connections to nurse cells at anterior end In other species, asymmetries occur after fertilization C. elegans – site at which sperm enters the egg Mammals – asymmetry doesn't occur until after four rounds of mitosis (16 cell embryo) Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 18

A Drosophila egg chamber
Somatic nurse cells connect to anterior part of oocyte Bicoid mRNA is transcribed in nurse cells, transported into oocyte, and associates with microtubules in oocyte Figure 18.32 Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 18

Cell-to-cell communication is essential for proper development
Cells must obtain information about their positions relative to other cells Ligand expressed by one cell binds to a receptor expressed on the surface of another cell Juxtracrine signaling – ligand is membrane-bound and interacts with a receptor on an adjacent cell Paracrine signaling – ligand is secreted and mediates long- range (e.g. hormones) or short-range signals (e.g. Wingless and hedgehog) Different ligand/receptor combinations active different signal transduction pathways Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 18

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