Differential Gene Expression in Development and Developmental Signals

How is it possible that such a diversity of cell types within a multicellular organism can be derived from single cell (the fertilized egg) ?

the chromosomes in each cell of an organisms body are the chromosomes established at fertilization.

Differential gene expression

the process by which cells become different from one another based on the unique combination of genes that are active

How can cells create different proteins that lead to the differentiation of different cell types

by expressing different genes

The postulates of differential gene expression

1. The DNA of all differentiated cells are identical

2. The unused genes are neither destroyed nor mutated and they retain the potential for being expressed

3. Only a small precentage of the genome is expressed in each cell

Gene expression

Cells can create different proteins that leads to the differentiation of different cell types

when was it established that gene expression can be regulated at 4 levels

1980

gene expression regulation level 1

differential gene transcription regulates which of the nuclear genes are transcribed into pre-messenger RNA

gene expression regulation level 2

Selective pre-messenger RNA processing regulates which parts of the transcribed RNAs can enter the cytoplasm and become messenger RNAs

gene expression regulation level 3

Selective messenger RNA translation regulates which of the mRNAs in the cytoplasm are translated into proteins

gene expression regulation level 4

Differential posttranslational protein modification regulates which proteins are allowed to remain and/or function in the cell

EMT

The Epithelial-Mesenchymal Transition

Epithelal cells

Adherent cells that form coherent layers and apico-basal polarity

Mesenchymal Cells

Non-polarized and lack intercellualr junctions, such that can move as individual cells throughout the extracellular matrix

What is the EMT

a process whereby epithelial cell layers lose polarity and cell-cell contacts and undergo a dramatic remodeling of cytoskeleton

What regulates signals from one cell being received by another cell

cell behavior such as adhesion, migration, differentiation and division

Signals are

Proteins

Cell Signaling

a complex system of communication that governs basic cellular activities and coordinates cell actions

What are the basis of development, tissue repair, and immunity as well as normal tissue homeostasis?

the ability of cells to perceive and correctly respond to their microenvironment

Error in cellular information

responsible for defects and diseases such as cancer, autoimmunity, and diabetes.

cell signaling classification

1. Autocrine

2. Paracrine

3. Endocrine

4. Juxtacrine

Autocrine signals

targets the cell itself and seen in placental cytotrophoblast cells

Paracrine signals

synthesized by one cell and can diffuse over a distance to induce changes in neighboring cells

Endocrine signals

target distant cells travelling through the blood to reach all parts of the body

Juxtacrine signals

target adjacent cells transmitting along cell membranes via protein or lipid components.

Morphogen gradient

One of the most important mechanisms governing cell fate specification involves gradients of paracrine factors that regulate gene expression

A morphogen

is a diffusible biochemical molecule that can determine the fate of a cell by its concentration

Four Major paracrine families

1. Fibroblast growth factor (FGF)

2. Hedghehog family

3. Wnt family

4. TGF-beta superfamily

Fibroblast Growth Factors (FGF)

that have been identified, and they can produce hundreds of protein isoforms by altering their RNA splicing or their initiation codons

FGF members

1. FGF 1

2. FGF 2

3. FGF 7

4. FGF 8

FGF1

important during regeneration

FGF2

angiogenesis

FGF7

Keratinocyte growth - critical for skin development

FGF8

limb development and lens induction

a pathway that is activated by FGFs

RTK pathway

The hedgehog family

multifunctional signal proteins that act in the embryo through signal transduction pathway to induce particular cell types and through other means to influence cell guidance

orginial hedgehog gene was found in

Drosophila

Vertebrates have at least 3 homologues hedgehog gene

1. Desert hedgehog (dhh)

2. Indian hedgehog (ihh)

3. Sonic hedgehog (shh)

Desert hedgehog (dhh)

expressed in Sertoli cells of testes

Indian hedgehog (ihh)

expressed in gut and in cartilage and also important for postnatal bone growth

Sonic hedgehog (shh)

responsible for assuring that motor neurons comes only from ventral portion of the neural tube

the receptor for the hedgehog family

patched

patched binds to a protein called

Smoothened

The WNT family

large family of cysteine-rich glycoproteins with at least 11 conserved members among vertebrates

the Wnt name

a fusion of the drosophila segment polarity with the names of one of its vertebrate homologues

the Wnt family was originally named

wingless

The Wnt family is involved in regulating

1. Specification of midbrain

2. Somites formation

3. Pollarity of insects and vertebrate limbs

4. Proliferation of stem cells

5. Several steps on urinogential system development

6. Regulating cell fates along the axis of various tissue

The TGF-beta superfamily include

1. Transforming growth factors - beta

2. The Nodal / activin family

3. Bone morphogenetic proteins (BMP)

4. Vg1 family

5. Glial-derived neurotrophic factor

6. Anti-Mullerian hormone

TGF-bet(1,2,3, and 5) are important for

1. extracellular matrix formation and for regulating cell division

2. epithelial branching that occurs in lung, kidney, and salivary gland development

BMP

distinguished by having seven conserved cysteines in the mature polypeptide

BMP regulates

1. Cell division

2. Cell migration

3. Cell differentiation

4. Apoptosis

5. Protein BMP4 ( for bone formation, specifies epidermis, cell death, etc)

6. Protein BMP7 ( for neural tube polarity, kidney development, and sperm formation)

NODAL / ACTIVIN are important in

1. different regions of the mesoderm

2. distinguishing the left and right sides of the vertebrate body axis

TGF-beta activate the

SMAD pathway

Transcription

Processing

Transport out of nucleus

Translation

Carry out functions

mRNA expressed in the brain and limb

mRNA expressed in the brain

mRNA expressed in the limb

Epithelial cells

Mesenchymal cells

Epithelial-Mesenchymal Transition

Autocrine

Juxtacrine signals

Paracrine

Endocrine

FGF ligand dimer

Homodimer of two FGFRs

A mutation in the gene for FGFR3 causes the premature constituitive activation of the STAT pathway, and the production of the phosphorated STAT1 protein

The hedgehog family

Morphogen gradient