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Looking for the appropriate size: genetics under control. Crazy about Biomedicine – May 2013 Ana Ferreira Development and Growth Control Lab. Summary. I. Genetics Definition Mendelian Genetics Drosophila melanogaster: The F ruit Fly Historical view of the fly - PowerPoint PPT Presentation
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Looking for the appropriate size: genetics under control
Crazy about Biomedicine– May 2013Ana FerreiraDevelopment and Growth Control Lab
I. Genetics
Definition Mendelian Genetics
Drosophila melanogaster: The Fruit Fly
Historical view of the fly Drosophila as a model organism
II. Developmental Biology
DefinitionHistorial view
III. Growth Control:
The different parameters Our system: the fly wing Systemic vs Organ-autonomous Growth Control
Size Control and Human Disease
Summary
I. Genetics
Genetics
Genetics deals with the molecular structure and function of genes,
gene behavior in the context of a cell or organism, patterns of
inheritance from parent to offspring, and gene distribution,
variation and change in populations
is a discipline of biology, is the science of genes, heredity, and variation in living organisms
GENETICS + ORGANISM EXPERIENCES
=
FINAL OUTCOME
Mendelian and Classic Genetics
Gregor Mendel(1822 - 1884)
observed that organisms inherit traits by way of discrete units of inheritance, which are now called genes
studied the nature of inheritance in plants
traced the inheritance patterns of certain traits in plants and described them mathematically
studied the segregation of heritable traits in pea plants
Pisum sativum
Discrete Inheritance and Mendel’s Laws
29,000 pea plants
Grow easily, develop pure-bred strains, and control their pollination
Discrete Inheritance and Mendel’s Laws
Discrete Inheritance and Mendel’s Laws
Dominant trait
Alleles: is one of a number of alternative forms of the same gene
Discrete Inheritance and Mendel’s Laws
Discrete Inheritance and Mendel’s Laws
3:1 ratio
diploid species: each individual has two copies of each gene, one inherited from each parent
organisms with two different alleles of a given gene are called heterozygous
organisms with two copies of the same allele of a given gene are called homozygous
Discrete Inheritance and Mendel’s Laws
(WW)
Purple
(Ww)
Purple
(ww)
White
heterozygoushomozygous homozygous
Discrete Inheritance and Mendel’s Laws
(WW)
Purple
(Ww)
Purple
(ww)
White
Genotype(set of alleles)
Phenotype(observable traits)
heterozygoushomozygous homozygous
one allele is called dominant
other allele is called recessive
W W
Discrete Inheritance and Mendel’s Laws
Discrete Inheritance and Mendel’s Laws
Discrete Inheritance and Mendel’s Laws
3:1 ratio
Discrete Inheritance and Mendel’s Laws
Discrete Inheritance and Mendel’s Laws
The Law of Dominance: In a cross between contrasting homozygous
individuals, only one form of the trait will appear in the F1 generation -
this trait is the dominant trait
1
Discrete Inheritance and Mendel’s Laws
The Law of Dominance: In a cross between contrasting homozygous
individuals, only one form of the trait will appear in the F1 generation -
this trait is the dominant trait
1
The Law of Segregation: when any individual produces gametes, the
copies of a gene separate so that each gamete receives only one copy
(allele) - a gamete will receive one allele or the other
2
The Law of Independent Assortment: alleles responsible for different
traits are distributed to gametes (and thus the offspring) independently
of each other
Discrete Inheritance and Mendel’s Laws
The Law of Dominance: In a cross between contrasting homozygous
individuals, only one form of the trait will appear in the F1 generation -
this trait is the dominant trait
1
The Law of Segregation: when any individual produces gametes, the
copies of a gene separate so that each gamete receives only one copy
(allele) - a gamete will receive one allele or the other
2
3
Drosophila melanogaster
Drosophila melanogaster: the fruit fly
Drosophila melanogaster: the fruit fly
Charles W. Woodworth (1865 - 1940)
1900 – First to breed Drosophila in the Lab
Historical view of Drosophila
Thomas Hunt Morgan (1866 - 1945)
1933 – Nobel Prize in Physiology or Medicine for the role played by chromosomes in heredity
1900 – Started to work with Drosophila (study of mutation)
1910 – First mutation was found (white)
Historical view of Drosophila
1911 – Genes are on chromosomes
Historical view of Drosophila
Hermann Joseph Müller (1890 - 1967)
1946 – Nobel Prize in Physiology or Medicine for the discovery of the genetics effects of Radiation (X-ray mutagenesis)
Historical view of Drosophila
Eric Wieschaus(1947 - )
Janni Nusslein-Volhard(1942 - )
Edward B. Lewis(1918 - 2004)
1995 – Nobel Prize in Physiology or Medicine for revealing the genetic control of embryonic development
Historical view of Drosophila
Jules A. Hoffmann(1941 - )
Bruce A. Beutler(1957 - )
Ralph M. Steinman(1943 – 2011)
2011 – Nobel Prize in Physiology or Medicine for the discovery of the dendritic cell and its role in adaptive immunity
Historical view of Drosophila
Why Drosophila melanogaster is such a good model organism ?
Why Drosophila melanogaster is such a good model organism ?
Short Life Cycle (Temperature Dependent – 10 days @ 25ºC)
Easy to maintain in the Lab (low cost)
Suitable of Genetic Manipulation
Simple karyotype: 4 pairs of chromosomes (3 autosomes + sexual chromosomes)
Extensive set of genetic tools available
Functional conservation of regulatory and biochemical pathways with humans
Gene Sequence Conservation with humans: 60%
Each Female lays 400-500 eggs
Why Drosophila melanogaster is such a good model organism ?
Easy to maintain and manipulate in the Lab (low cost)
Suitable of Genetic Manipulation
Simple karyotype: 4 pairs of chromosomes (3 autosomes + sexual chromosomes)
Extensive set of genetic tools available
Functional conservation of regulatory and biochemical pathways with humans
Gene Sequence Conservation with humans: 60%
Short Life Cycle (Temperature Dependent – 10 days @ 25ºC)
Each Female lays 400-500 eggs
Why Drosophila melanogaster is such a good model organism ?
Easy to maintain and manipulate in the Lab (low cost)
Suitable of Genetic Manipulation
Simple karyotype: 4 pairs of chromosomes (3 autosomes + sexual chromosomes)
Functional conservation of regulatory and biochemical pathways with humans
Gene Sequence Conservation with humans: 60%
Extensive set of genetic tools available
Short Life Cycle (Temperature Dependent – 10 days @ 25ºC)
Each Female lays 400-500 eggs
Why Drosophila melanogaster is such a good model organism ?
Suitable of Genetic Manipulation
Simple karyotype: 4 pairs of chromosomes (3 autosomes + sexual chromosomes)
Functional conservation of regulatory and biochemical pathways with humans
Gene Sequence Conservation with humans: 60%
Extensive set of genetic tools available
Easy to maintain and manipulate in the Lab (low cost)
Short Life Cycle (Temperature Dependent – 10 days @ 25ºC)
Each Female lays 400-500 eggs
Why Drosophila melanogaster is such a good model organism ?
Suitable of Genetic Manipulation
Simple karyotype: 4 pairs of large chromosomes (3 autosomes + sexual chromosomes)
Functional conservation of regulatory and biochemical pathways with humans
Gene Sequence Conservation with humans: 60%
Extensive set of genetic tools available
Easy to maintain and manipulate in the Lab (low cost)
Short Life Cycle (Temperature Dependent – 10 days @ 25ºC)
Each Female lays 400-500 eggs
Why Drosophila melanogaster is such a good model organism ?
Suitable of Genetic Manipulation
Simple karyotype: 4 pairs of large chromosomes (3 autosomes + sexual chromosomes)
Functional conservation of regulatory and biochemical pathways with humans
Gene Sequence Conservation with humans: 60%
Extensive set of genetic tools available
Easy to maintain and manipulate in the Lab (low cost)
Short Life Cycle (Temperature Dependent – 10 days @ 25ºC)
Each Female lays 400-500 eggs
Why Drosophila melanogaster is such a good model organism ?
Drosophila melanogaster Life Cycle
Growth Phase
Drosophila melanogaster: why is such a potent genetic organism ?
Mutant animals are readily obtainable
Targeting gene expression in a temporal and spatial fashion
Genome fully sequenced
Huge amount of transgenic lines available
Driver line Responder line
Big collection of both Driver and Responder Lines available
Temperature Dependence of the Driver Line
Targeting gene expression: Gal4-UAS System
Targeting gene expression: Gal4-UAS System
Targeting gene expression: Gal4-UAS System
II. Developmental Biology
Developmental Biology
Historical Perspective – The first steps
Aristotle (384 – 322 AC)
Study of the Development of the chick
The semen of the male provides the “form” or soul and the female the unorganized matter (menstrual blood) allowing the embryo to grow: EPIGENESIS
Theory of Preformationism: organs with their own shape expand
Theory of Spontaneous Generation: life of invertebrates emerges from non-living matter (“nothing”)
Views of a Fetus in the WombLeonardo da Vinci, ca. 1510-1512
Dissection of human corpses
Drawings of the vascular and system
First drawing of the human fetus in theutero
Historical Perspective - Renaissance
Leonardo da Vinci (1452 - 1519)
Historical Perspective - Renaissance
Historical Perspective - Renaissance
Antonie van Leeuwenhoek(1632 - 1723)
“…now that I have discovered that the animalcules also occur in the male seed of quadrupeds, birds and fishes…, I assume with even greater certainty than before that a human being originates not from an egg but from an animalcule that is found in the male semen”
Discovered the microorganisms: animacules
Discovered the spermatozoa
Nicolaas Hartsoeker in 1695
Historical Perspective - Renaissance
PREFORMATIONISM
organisms develop from
miniature versions of themselves
Historical Perspective - Renaissance
Discovered the follicles of the ovary (known as
Graafian follicles), in which the individual egg
cells are formed
Reiner de Graaf(1641 - 1673)
Rejecting the preformationism
Historical Perspective
Ernst Haeckel(1834 - 1919)
Recapitulation Theory /
Embryological Parallelism
developing from embryo to
adult, animals go through
stages resembling or
representing successive
stages in the evolution of
their remote ancestors
"ontogeny recapitulates phylogeny”
Opposing view that the early general forms
diverged into four major groups of specialized
forms without ever resembling the adult of
another species
Karl Ernst von Baer(1792 - 1876)
Historical Perspective
August Weismann(1834 - 1914)
Historical Perspective
Germ plasm theory
inheritance only takes place by means of the germ cells—the gametes
Other cells of the body—somatic cells—do not function as agents of heredity
Historical Perspective
Experimental Embryology
Wilhelm Roux1888 – Experiment destroying the frog embryo (in the two cells stage)
Hans Driesch1892 – Separates de early 4 cells stage embryo of the sea urchin
Hans Spemann and Hilde Mangold1918-1924 – Transplants of cells from one embryo to another induced particular
tissues or organs – embryonic induction. Nobel Prize in 1935
Are Developmental Biology and Genetic Linked ?
III. Growth Control
How are differences in size achieved ?
What determines differences in size ?
Size of an organ/animal =
similarSize of an organ/animal = number of cells + size of the cells
Cell Number
Cell Size
Cell Number+
Cell Size
Cell Division+
Cell Death
Cell Growth
number of cells + size of the cells + space between cells
Cell Division / Proliferation: increase in cell number by one cell (the
"mother cell") dividing to produce two "daughter cells"
Cell Death / Apoptosis: is death of a cell in any form, mediated by an
intracellular program (DNA fragmentation and protein degradation)
Cell Growth: increase in cell mass (protein synthesis and organelle
biogenesis)
What determines differences in size ?
Cell Cycle
How organs achieve a particular size and pattern ?
Drosophila imaginal discs: proliferative tissues
notum
wing
20-30 cells
50,000 cells
Drosophila wing imaginal disc
Embryo
Larvae
Adult
Drosophila wing imaginal disc development
Body Size Regulation
Cell autonomous growth promoters
Morphogens, signaling molecules
Long range signaling molecules (hormones…)
Environmental factors (nutrition…)
Systemic vs organ-autonomous growth control
Systemic growth control
SYSTEMIC GROWTH CONTROL
GROWTH RATE DEVELOPMENTAL TIMING(moults+pupariation)
Gut
Fat body
Brain
Ring gland
nutrients
Insulin
GROWTH
Systemic growth control
FEEDING
Hemolymph (fly ‘blood’)
Ecdysone
DEVELOPMENTAL TIMING
Organ-autonomous growth control
Regeneration Experiments
Transplants Experiments: when a small organ is transplanted into an adult
organism it grows to its normal final size (even in between different species)
Size Control and Human Disease
Cancer: tumor initiation,
metastasis
Diabetesand
Obesity
Organ hypertrophy or atrophy
Insulin pathwaydMyc oncogeneHippo pathway
TGFb signaling (Dpp)Wnt signaling (Wg)
Regenerationand Stem
Cell Biology
Growth Pathways
Drosophila was, is and will be important for Human Biology
Crazy aboutB omedicine
Thank you
Development and Growth Control Lab
Transformation in flies