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Developmental Genetics

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Title: Developmental Genetics Author: Korakod Last modified by: Korakod Created Date: 10/25/2000 9:53:00 AM Document presentation format: On-screen Show – PowerPoint PPT presentation

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Title: Developmental Genetics


1
Developmental Genetics
2
Developmental Genetics
  • Topics
  • I. Genetic Basis of Differentiation
  • II. Control of Gene Expression in
  • Differentiation
  • III. Nature of Determination

3
Development ??? organism
  • ????????????? Single fertilized egg cell ????
    embryo ????????? adult
  • Adult ?????????? cells ????????? trillions (1012)
  • ??????????????????????? organs ???? ?
  • Organ ?????????? tissues ????????? ?
    ???????????????????????????????
  • Tissue ??? ?????????????????????????
    ???????????????

4
  • Cell Differentiation

5
  • Embryonic development ??? Amphioxus

6
Differentiation
  • ????????????? ?????????????? (specialized
    characteristics) ???????? type ???? ?
  • Specialized cellular functions ???????
  • 1) Proteins structural proteins for cell
    shapes
  • 2) Enzymes specific chemical reactions
  • 3) Hormones signals from cell to cell

7
Genetics ??? Developmental Pathway
  • ????????? ???? Mutation
  • Developmental pathway ?????????????????????
    differentiation
  • ????????????????????? tissues ??? organs
    ????????? Phenotypes ??? differentiated cells

8
  • ????????????? Developmental pathway
  • Different gene products
  • Signal molecules signal receptors
  • Cytoplasmic proteins signal transducers
  • Transcription factors
  • Regulator proteins

9
I. Genetic Basis of Differentiation
10
I. Genetic Basis of Differentiation
  • 1. Theory of development
  • 1.1 Theory of Mosaic Development
  • 1.2 Theory of Regulative Development
  • 2. Substances of development
  • 2.1 Determinants
  • 2.2 Inducers
  • 2.3 Morphogens

11
Genetic Basis ??? Cell Differentiation
  • Early embryonic cells ?????????????????????
    ?????????????????
  • Differentiated cells ???? specialized products
    2 ?????????
  • 1) Fundamental proteins ????????? (vital)
    ???????????
  • Housekeeping genes RNA polymerases
  • ribosomal proteins
  • 2) Specialized cell products ????????? organs
    ???
  • Luxury genes hemoglobin, insulin

12
Theory of Development
13
1. Theory of Development
  • ?? 2 ????? ??????????????? Expression ??? genes
    ??????? development ????????????????????????????
  • gene ????? express ????????????????
  • gene ???? express ??????????????????
  • 1.1 Theory of Mosaic Development
  • 1.2 Theory of Regulative Development

14
1.1 Theory of Mosaic Development
  • Differentiation ??? embryonic cells
    ????????????????? genetic potential
    ??????????????????????? ? ?????????????????????
  • ??????? cell cycle ??????? development
    ???????????????? genetic material ??????? --gt
    ?????????????????
  • ?????????????????????? organism
    ?????????????????????????????? (mosaic)
  • Embryo ???????? Mosaic embryo

15
  • ??????? ???????????????? Genes ???????????????
  • genes ?????????????? potential ???????
    differentiation ?? ????????
  • 1. Housekeeping genes ???
  • 2. Luxury genes
  • ?? invertebrate ??????????????????????? embryo
    ??????????? 2 ????? ?????? ???
  • ???????? programmed ?????? ???????????
    differentiate ?????? ?????????? ???? ??????????

16
1.2 Theory of Regulative Development
  • ????? embryo ??? eukaryote ???????????????????????
    ?????? 8 cells ???????????????????????
  • ???? 8 ??????????? develop ???? 8 organisms
  • ???????????????????????? 8 ????????? (regulated)
  • ?????????????? Totipotent ??? ??????? genetic
    materials ?????????? ????????????????????? 8
    ??????????
  • Embryo ???????? Regulative embryo

17
  • ??????? ????? embryo ????? genetic materials
    ????????????? ?????????????? 3 cell division
    cycles ??????????????????? mosaic development
  • ?????????????? ???????? Regulative development
  • ???? embryo ??? humans ????????????????????????
    ? (??? 8 ??)

18
  • ??????????????? totipotency ????????? ???
  • ?? totipotent ???? stem cells/ precursor cells
    ??? ????????????????????????
  • ??????? genetic potential ????????? ???? muscle
    cells ??? nerve cells
  • ????? adult cell ????? 1 ????? ???? totipotent
    differentiated cells ????????????????????????????
    ?????????????????????? tissue culture

19
  • ??????? animals plants
  • ????????? totipotent differentiated cells
    ????????????
  • ????????????????? genetic material ??
    differentiation ???????? ???????????? ???
  • ?????????????????????? genes ???????
  • cell differentiation
  • ??????????????????? cell differentiation
    ??????????? Epigenetic changes ???????????????????
    ?
  • gene expression ???????????? genes ??????

20
Substances in Development
21
2. 1 Determinant
  • ????????? differentiate ??? express specific
    function ?????????????????????? Determination
  • Determination ???????????????????? point of no
    return ???? irreversible commitment ??
    Development program ???? fate ????????????????????
    ??
  • ??????? ??? Effector substances ?? cytoplasm
    ????? ???? Determinants

22
  • Gradient of determinations determinants ??????
    egg ??????????????????????????????????????????????
    ?? (gradient) ??? ?? --gt ???? (animal pole --gt
    vegetal pole) ?????? side --gt side

23
  • Determinants ??????? Maternal messages
  • mRNA ????????????????????????????????????????????
    ??????????? egg (developing egg) ????
  • Determinants ??????? Transcription factors
    ????????????? egg
  • ???????????????? embryonic cells ??? embryo
    ??????????

24
2.2 Inducers
  • Substance ??????????????????????????????????????
  • ??????????????????????????? ???? ???? Signal
    ??? cell ??? cell ????
  • ?????????? embryo 3 ???? Mesoderm ?? induce
    development ??? Ectoderm
  • ?????????? induce ??????????? ??????????

25
2.3 Morphogens
  • ???? subsets ??? determinant ??? inducer
  • Morphogen ????????????? (morphology) ??? embryo
    ?????????????
  • Morphogen ????????????????????????????????????????
    ? embryo ?????????? transplantation
  • ???? ?? chick limb bud ?? Retinoic acid
    ????????????????????? ???????? (digits)

26
  • ????? Retinoic acid ???? morphogen
    ??????????????????????????????????????????????????
    ????
  • Retinoic acid ????????????????????? hormones
    ?????? differentiation ???????

27
II. Control of Gene Expression in Differentiation
28
II. Control of Gene Expression in Differentiation
  • Differentiation ?????????? turn-on ??? genes
  • ????????????
  • ???? control ??? structural gene expression ?????
  • Transcription,
  • Posttranscription,
  • Translation ???
  • Posttranslation

29
Control ?? Prokaryote
  • ?????????????????????????? gene expression ???
    cellular activity
  • ???? ?? bacteria ???????? Sporulation
  • --gt Vegetative
  • ??????????????? sigma (s) factor ??? RNA
    polymerase ??? ??????????????

30
Control ?? Eukaryote
  • Expression ??? luxury genes
  • 1. Hormone activation of genes
  • 2. Hormone-responsive elements
  • 3. Light-induction of plant genes

31
1. Hormone Activation on Genes
  • Hormone ???????? turn on transcription ???
    specific genes ?? target cells ???
  • 1. ?????? ??? ???????????? genes ?? nucleus
  • 2. ??????? ??????? second messenger ??? cell
    membrane ?????? cytoplasm
  • Hormone action ???? complex process ???? 2 ????
    ?????? receptor ????????? hormone

32
Steroid Hormone
  • Steroid hormone ?????????????? development ???
    differentiation
  • Steroid hormone ??????? cell membrane ????
    cytoplasm ???? nucleus ???????? receptor ??
    nucleus
  • Hormone-receptor complex ????? chromatin ??
    activate genes ?????????????????? Transcription

33
  • Effect ??? Steroid Hormone ??? Gene Expression

34
Activation ??? Estrogen ??? Ovalbumin Gene ??
chick oviduct
  • estrogen-receptor complex ?? binding site
    ?????????? 250-300 base pairs upstream ??? TATA
    box
  • hormone-receptor complex ????? transcription
    factor ??? bind ??? stimulate ?????????? enhancer
    ??? gene

35
Hormone ??????? family ????? receptor ?? nucleus
  • ?????????????????? development
  • 1) Glucocorticoid receptor mediate gene ???
  • hormone cortisol
  • 2) Vitamin D3 receptor
  • 3) Thyroid hormone receptor
  • 4) Retinoic acid receptor
  • Response ???????? ???????????? receptor ???????

36
2. Hormone-Responsive Elements (HRE)
  • ??? Enhancer ???????????? receptor ??? hormone
    ??????? hormone-receptor complex
  • Enhancer ?????????????????????? Promotor ??? gene
    ???????? RNA polymerase ?? transcription ?? gene
    ???
  • ???? HRE ?????? hormone ??? receptor ????????

37
2.1 HRE ?????? Retinoic Acid Receptor Retinoic
acid responsive element (RARE)
  • ???? binding site ?? DNA
  • ?????????
  • Retinoic acid receptor (RAR)
  • RAR ???????????????????
  • ???????? Finger protein
  • ?????? 2 Zinc fingers

38
  • Retinoic acid receptor (RAR) protein
  • ?????? Retinoic acid responsive element (RARE)
  • DNA sequence ??? RAR-RARE complex ?? DNA
  • ???? Retinoic acid (R) ????????????? RAR-RARE
    complex
  • RAR-RARE complex ????? stimulate gene
    ???????????
  • RARE ???? growth hormone gene ?????? pituitary
    ???????? growth hormone

39
Action ??? Retinoic Acid
  • RAR (receptor) RARE (element)
  • RAR-RARE Complex /----Promotor-----Gene-----/
  • /-------RAR-RARE-Promotor-----Gene----
    -/ Transcription
  • Retinoic Acid RNA Polymerase

40
(No Transcript)
41
2.2 HRE ?????? Thyroid hormone receptor (THR)
  • RARE ???? enhancer ??? Thyroid hormone receptor
    (THR) ????
  • ????? thyroid hormone ???????????? retinoic acid
    ????? ????????????? growth hormone
  • ??? thyroid hormone receptor ?????? RAR ???
    dimer ????? growth hormone RARE --gt turn on
    growth hormone gene --gt growth hormone

42
2.3 RARE ???? Enhancer ??? Vitamin D3 Receptor
  • Vitamin D3 ???????????? Retinoic acid
  • ????????? VDR ??? RAR ???????? ??? RARE
  • ??????? turn on Osteocalcin gene --gt product
    ????????? differentiation ??? immature
    Osteoblasts
  • Osteoblasts uptake calcium
  • Osteoblasts differentiate ???? mature Osteocytes

43
?????????? Cells ??????? response ???
hormone???????????? ????? ??
  • hormone receptor ??????????? specificity ???????
  • Hormones ????????? target ????? 2-3 cell types
  • ???? Retinoic acid ?? vertebrate ?? receptor 3
    types
  • ????? type RARa ???????????????????????
  • Retinoic acid ??????? Morphogen ???????
  • Hormone receptor ??????? protein ???????????
    differentiation ???????????

44
3. Light-induction of plant genes
  • ??????? (Seedling) ????????????????????
    ?????????? photosynthetic apparatus ???????
    chlorophyll ???????????????????
  • ?????????????? seedling ????????????????????? ???
    enzyme ????? chlorophyll ???? light-activated
    enzyme ???? Ribose biphosphate carboxylase ????
    Rubisco

45
Rubisco Gene
  • ????????? Rubisco gene ??? light-inducible genes
  • Promoter
  • ??? -35 base pair region ?? TATA box
  • Sequence ??? -35 ??? -46 ???? light dependent ???
  • ?????????? -46 upstream ????????????????
  • Enhancer
  • Region ??? -327 ??? -48 ???? stimulate rubisco
    gene ??????????????????

46
Promoter enhancer ??? Light response gene
  • (a) Rubisco gene ??? pea cloned ??? petunia cells
  • (b) Rubisco gene ??? pea cloned ??? tobacco

47
Control Expression ??? gene ?? cell
differentiation ?? plants ??? animals
  • Regulatory region / 5-flanking region ???
  • cis-acting DNA ??? Control region
    ????????????????? structural gene ???? TATA box
    ??? GC box
  • trans-acting protein ???? transcription factor
    ????? DNA ????????????? template

48
III. Nature of Determination
49
Determination
  • ??? ????????????????????????????? ???????? cell
    ??????????? developmental pathway
  • ????????????????????????????????????????
    Chromatin ??? factor ??????? histones ????????
    control regions ??? genes

50
???? Determination
  • 1. DNase Hypersensitivity
  • 2. Control expression ??? 5S rRNA
  • 3. DNA methylation

51
1. DNase Hypersensitivity
  • DNA ????????????? Nucleosomes (300 bp) ??
    chromatin ??????????? histones ??????? DNas
    ???????? DNase hypersensitive site

52
  • DNase hypersensitive region ????? 5- flanking
    region / regulatory region (promoter enhancer)
  • ????????? turn on/off gene ????????? factor
    (protein) ??????????????????? hypersensitivity
    ?????????????? Nucleosome ????
  • globin gene ??????????????
  • Hypersensitivity region ??? 60-260
    upstream??????????????? nucleosome ????? embryo
    ???? 14 ???
  • ?? Determination factor ??? globin gene active
    ????????? 14 ????????????

53
2. Control ??? 5S rRNA gene expression
  • 5S rRNA genes (??) ?? 20,000 genes ????????
  • 2 family
  • 1. Oocyte 5S rRNA genes 98 , transcription
    ????
  • ????? ?? oocytes
  • 2. Somatic 5S rRNA genes 2 , transcription
    ????
  • ?? somatic cells

54
Expression ??? rRNA genes 2 families
  • ???? replication ??????????? cell division
    ??????????????????????????
  • transcription factors RNA Pol III ?? factors ???
    TFIIIA, TFIIIB, ??? TFIIIC ???
  • histones ?? hypersensitivity region
  • ???? ?? immature egg ??? developing embryo ?????

55
  • ?? immuture egg
  • Oocyte 5S rRNA genes express ???
  • somatic 5S rRNA genes ??? repressed
  • ?? developing embryo Embryo 3,200 cells
  • TFIIIA ???????????????? ??????? 1 ??????? /
    oocyte rRNA gene
  • ????? oocyte rRNA gene ??? repressed ??? histones
    ??? somatic rRNA gene ????? express

56
3. DNA methylation
  • Active genes ?????? low methyl groups ???? ?????
  • Methylation ??? DNA
  • ????? repress gene ????????????? ???
  • ???? signal ??? DNA ????????? methylation ????
  • ?? methylation ?? higher eukaryote ??????????? C
    ??????? 5-CG-3 dinucleotides

57
Determination ??? mehtylation
  • ????? 1) Repress gene activity ???
  • 2) permanent
  • ??????? Epigenetic mechanism ????? methylation
    ??????????????? genetic ???
  • ????? gene turn off ??????????? development ????
  • X chromosome ?? female ???????? methylated ???
    ???? develop ????
  • Inactive X chromosome ??????????? Lyonized
  • ???????????????????? Barr body

58
Genes ??????? Determination
  • ?? ???????? ?????????? mutation
  • ?? genes ???????????? determination
    ????????????????????? ????????
  • Homoeotic genes ???? Homeotic genes
  • ?????????? mutation ?????????????????????????????
    (transformation) ?????????????????????????????????
    ???????

59
  • ???? Antennapedia (Antp) mutant
    ????????????????????
  • ??????? genes ??? cells ?????????????
    ???????????????????????? ???? cells ??????????
    develop ?????????????? programmed ??? develop
    ??????
  • Transformation ????????????? activity ???????
    genes
  • ???????????? gene ????????????? mutated ????????
    transformation
  • ??????? gene ??????? control genes ????? ???
    develop ???????? Homeotic gene

60
  • ??????? Homeotic gene ???? Master gene
    ???????????????? determination ???? (fate)
    ???????????????????????????????????
  • ??? mutate gene ?????????? determination
    ???????????????? / program????
  • Homeotic genes ?????????????? ?????????
    development
  • ????????????????? Homeotic gene ???? 2 ????? ???
  • Antennapedia complex (ANT-C) ???
  • Bithorax complex (BX-C)

61
Homeobox
  • Common DNA sequence ?????? 180 bp ??
  • ?? Homeotic genes ???? complex (cluster) genes
    ???
  • ?? Non-homeotic genes ???????????????????
    transform ??? body part ??????????????????????????
    ?? homeotic genes ????? development
    ?????????????????????????? embryo

62
????????? Homeobox
  • 75 - 79 conserved
  • share ??? control genes ??????? develop
    ????????????????
  • code ??? protein ????? DNA-binding domain ???????
    positively charged ???
  • protein ???????? transcription factor ?? migrate
    ???????? nucleus ????? control region ??? genes
    ????????????

63
Arrangement ??? homeobox genes
  • ????????????? vertebrate ??? invertebrate ???
  • ???????? anterior-posterior body axis ??? express
    ???
  • genes ?????????????????? cluster ???? genes ???
    express ????????? (anterior) ???
  • genes ?????????????? cluster ??? express
    ????????????? (posterior)

64
Maternal Effect Genes
  • Genes ??? code ??? products ?? egg ???? ??????
    ??? products ???????????????????? ???? ????? egg
    ?? polarity
  • products ?? effect ??? development ??? body parts
  • bicoid (bcd) gene ??????? anterior body parts
    ???? heads thoraxes

65
Segmentation genes
  • Control organization ?????????????????? segments
  • ftz gene ?? segment ???? segment ???? pair-rule
    genes ????????? embryo ???????
  • engrailed gene ???? embryo ??????? anterior
    posterior

66
Vertebrate homeoboxes
  • sequence ??? homeoboxes ??? ??????????????
    vertebrate ?????????????? 95
  • ?????????????? genes ???? cluster
    ?????????????????? express
  • homeotic genes ???????????????? clusters express
  • ?????????? ???
  • homeotic genes ????????????????? clusters express
    ??????????

67
  • homeobox gene ??? vertebrate active ??????????
    active ??????????????? differentiation
  • homeobox proteins ?? vertebrates ????????
    Transcription factor ??? Regulator ?? development
    ??? embryo
  • ???? Pit -1 protein

68
  • Pit -1 protein ?? mouse dwarf (dw) gene
  • ?????? development ??? pituitary glands ????????
    growth hormone, prolactin hormone ???
  • thyroid - stimulating hormone
  • ??????? Pit-1 ?? multiple effects ??? development
  • ??? pituitary gland

69
  • Developmental pathway
  • House keeping genes Luxury genes
  • Mosaic development vs. Regulative development
  • Totipotency vs. Epignetics
  • Determinants, Inducers Mophogens
  • Differentiation control in Prokaryote vs.
    Eukaryote
  • Animal Hormone-induced genes Hormone
    responsive element
  • Plant Light-induced genes
  • DNA hypersensitivity, rRNA gene expression, and
    DNA methylation
  • Homeotic genes Homeobox
  • Maternal Effect genes
  • Segmentation genes
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