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Developmental Genetics. Developmental Genetics. Topics : I. Genetic Basis of Differentiation II. Control of Gene Expression in Differentiation III. Nature of Determination. Development ของ organism. การเจริญพัฒนา Single fertilized egg cell เป็น embryo และไปเป็น adult

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Developmental Genetics

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Developmental

Genetics


Developmental Genetics

Topics :

I. Genetic Basis of Differentiation

II. Control of Gene Expression in

Differentiation

III. Nature of Determination


Development organism

  • Single fertilized egg cell embryo adult

  • Adult cells trillions (1012)

    organs

  • Organ tissues

  • Tissue


Cell Differentiation


Embryonic development Amphioxus


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


Genetics Developmental Pathway

  • Mutation

  • Developmental pathway differentiation

  • tissues organs Phenotypes differentiated cells


  • Developmental pathway

    • Different gene products

    • Signal molecules : signal receptors

    • Cytoplasmic proteins : signal transducers

    • Transcription factors

    • Regulator proteins


I. Genetic Basis of Differentiation


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


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


Theory

of

Development


1. Theory of Development

2 Expression genes development

  • gene express

  • gene express

    1.1 Theory of Mosaic Development

    1.2 Theory of Regulative Development


1.1 Theory of Mosaic Development

  • Differentiation embryonic cells genetic potential

  • cell cycle development genetic material -->

  • organism (mosaic)

  • Embryo Mosaic embryo


  • Genes

  • genes potential differentiation

    1. Housekeeping genes

    2. Luxury genes

  • invertebrate embryo 2

  • programmed differentiate


1.2 Theory of Regulative Development

  • embryo eukaryote 8 cells

  • 8 develop 8 organisms

  • 8 (regulated)

    Totipotent genetic materials 8

  • Embryo Regulative embryo


  • embryo genetic materials 3 cell division cycles mosaic development

  • Regulative development

    embryo humans ( 8 )


totipotency

  • totipotent stem cells/ precursor cells

  • genetic potential muscle cells nerve cells

    adult cell 1 totipotent differentiated cells tissue culture


: animals & plants

  • totipotent differentiated cells

  • genetic material differentiation

  • genes

    cell differentiation

  • cell differentiation Epigenetic changes

    gene expression genes


Substances

in

Development


2. 1 Determinant

  • differentiate express specific function Determination

  • Determination point of no return irreversible commitment Development program fate

  • Effector substances cytoplasm Determinants


  • Gradient of determinationsdeterminants egg (gradient) --> (animal pole --> vegetal pole) side --> side


  • Determinants Maternal messages

  • mRNA egg (developing egg)

  • Determinants Transcription factors egg

  • embryonic cells embryo


2.2 Inducers

  • Substance

    Signal cell cell

  • embryo 3 Mesoderm induce development Ectoderm

  • induce


2.3 Morphogens

  • subsets determinant inducer

  • Morphogen (morphology) embryo

  • Morphogen embryo transplantation

  • chick limb bud Retinoic acid (digits)


  • Retinoic acid morphogen

  • Retinoic acid hormones differentiation


II. Control of Gene Expressionin Differentiation


II. Control of Gene Expression in Differentiation

  • Differentiation turn-on genes

  • control structural gene expression

    • Transcription,

    • Posttranscription,

    • Translation

    • Posttranslation


Control Prokaryote

  • gene expression cellular activity

  • bacteria Sporulation

    --> Vegetative

  • sigma (s) factor RNA polymerase


Control Eukaryote

Expression luxury genes

1. Hormone activation of genes

2. Hormone-responsive elements

3. Light-induction of plant genes


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


Steroid Hormone

  • Steroid hormone development differentiation

  • Steroid hormone cell membrane cytoplasm nucleus receptor nucleus

  • Hormone-receptor complex chromatin activate genes Transcription


Effect Steroid Hormone Gene Expression


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


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


2. Hormone-Responsive Elements (HRE)

  • Enhancer receptor hormone hormone-receptor complex

  • Enhancer Promotor gene RNA polymerase transcription gene

  • HRE hormone receptor


2.1 HRE Retinoic Acid Receptor Retinoic acid responsive element (RARE)

binding site DNA

Retinoic acid receptor (RAR)

RAR

Finger protein

2 Zinc fingers


  • 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


Action Retinoic Acid

RAR (receptor) + RARE (element)

RAR-RARE Complex /----Promotor-----Gene-----/

/-------RAR-RARE-Promotor-----Gene-----/ Transcription

Retinoic AcidRNA Polymerase


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 --> turn on growth hormone gene --> growth hormone


2.3 RARE Enhancer Vitamin D3 Receptor

  • Vitamin D3 Retinoic acid

  • VDR RAR RARE

  • turn on Osteocalcin gene --> product differentiation immature Osteoblasts

  • Osteoblasts uptake calcium

  • Osteoblasts differentiate mature Osteocytes


Cells response hormone

  • hormone receptor specificity

  • Hormones target 2-3 cell types

  • Retinoic acid vertebrate receptor 3 types

  • typeRARa

  • Retinoic acid Morphogen

  • Hormone receptor protein differentiation


3. Light-induction of plant genes

  • (Seedling) photosynthetic apparatus chlorophyll

  • seedling enzyme chlorophyll light-activated enzyme Ribose biphosphate carboxylase Rubisco


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


Promoter & enhancer Light response gene

(a) Rubisco gene pea cloned petunia cells

(b) Rubisco gene pea cloned tobacco


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


III. Nature of Determination


Determination

  • cell developmental pathway

  • Chromatin factor histones control regions genes


Determination

  • 1. DNase Hypersensitivity

  • 2. Control expression 5S rRNA

  • 3. DNA methylation


1. DNase Hypersensitivity

  • DNA Nucleosomes (300 bp) chromatin histones DNas DNase hypersensitive site


  • 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


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


Expression rRNA genes 2 families

  • replication cell division

    • transcription factors RNA Pol III factors TFIIIA, TFIIIB, TFIIIC

    • histones hypersensitivity region

      • immature egg developing embryo


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


3. DNA methylation

  • Active genes low methyl groups

  • Methylation DNA

    • repress gene

    • signal DNA methylation

  • methylation higher eukaryote C 5-CG-3 dinucleotides


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


Genes Determination

  • mutation:

    genes determination

    Homoeotic genesHomeotic genes

  • mutation (transformation)


  • Antennapedia (Antp) mutant

  • genes cells cells develop programmed develop

    • Transformation activity genes

    • gene mutated transformation

  • gene control genes develop Homeotic gene


  • Homeotic gene Master gene determination (fate)

    • mutate gene determination / program

  • Homeotic genes development

  • Homeotic gene 2

    • Antennapedia complex (ANT-C)

    • Bithorax complex (BX-C)


Homeobox

Common DNA sequence 180 bp

  • Homeotic genes complex (cluster) genes

  • Non-homeotic genes transform body part homeotic genes development embryo


Homeobox

  • 75 % - 79 % conserved

  • share control genes develop

  • code protein DNA-binding domain positively charged

  • protein transcription factor migrate nucleus control region genes


Arrangement homeobox genes

vertebrate invertebrate

  • anterior-posterior body axis express

    • genes cluster genes express (anterior)

    • genes cluster express (posterior)


Maternal Effect Genes

Genes code products egg products egg polarity

  • products effect development body parts

  • bicoid (bcd) gene ~ anterior body parts heads & thoraxes


Segmentation genes

Control organization segments

  • ftz gene segment segment pair-rule genes embryo

  • engrailed gene embryo anterior & posterior


Vertebrate homeoboxes

  • sequence homeoboxes vertebrate 95%

  • genes cluster express

    • homeotic genes clusters express

    • homeotic genes clusters express


  • homeobox gene vertebrate active active differentiation

  • homeobox proteins vertebrates Transcription factor Regulator development embryo

    • Pit -1 protein


Pit -1 protein mouse dwarf (dw) gene

  • development pituitary glands growth hormone, prolactin hormone

    thyroid - stimulating hormone

    Pit-1 multiple effects development

    pituitary gland


  • 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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