Embryonic induction refers to the ability of embryonic cells to influence each other during development.

This is achieved through cell-to-cell signaling systems. A signal transduction pathway is activated within the cell, leading to activation or repression of specific genes or to changes in cell behavior mediated through the cytoskeleton or through changes to cellular metabolism.

Member TGF-F1 t F5

Represent ti e F ncti ns Mesodermal induction; myoblast proliferation; invasion of cardiac jelly by atrioventricular endot elial cells Granulosa cell proliferation Inhibition of onadotropin secretion by hypophysis Regression of paramesonephric ducts Signaling in limb development Mesodermal induction Formation of the neural plate, skeletal differentiation, and other inductive interactions Formation of primitive streak and left-right axis of embryo Induction of outgrowth of ureteric bud

Activin Inhibin Mullerian inhibiting substance Decapentaplegic Vg1 Bone morphogenetic protein1 to 9 Nodal Glial cell line-derived neutrotropic factor

Families of Inducing Factors employ specific pathways of signal transduction 1. Transforming growth factorF superfamily (TGFFs)- about 30 genes controlling embryogenesis & postnatal life.  The ligand binds to a type II receptor, enabling it to form a complex with a Type I receptor.  Activation causes phosphorylation of smad proteins in the cytoplasm, causing smads to migrate to the nucleus where they act as transcription factors.  Smad 1, 5, 6, 8 are targets for BMP receptors; smads 2, 3 for activin receptors; smad 6 and 7 inhibit both pathways by displacing the binding of smad 4.

 Chordin and Noggin dorsalize mesoderm. They are both found in the dorsal lip of the blastopore and convert otherwise epidermis specified tissue into neural tissue. Noggin plays a key role in cartilage and bone patterning. Mice Noggin-/- have excess cartilage and lacked joint formation.  Cerberus of the DAN family inhibits BMP activity which include development of the heart, CNS, and cartilage, as well as post-natal bone development.  Follistatin inhibits Activin, which it binds. It directly affects FSH secretion. Follistatin mutations are implicated in prostate cancers preventing it from acting on activin which has anti-proliferative properties.  Lefty is involved in plays a role in left-right specification during embryogenesis. Lefty acts by preventing the phosphorylation of R-SMADs.

2. Fibroblast growth factor family (FGF)- monomeric polypeptides that bind tightly to heparan sulfate, a GAG on cell membranes.  The FGF-heparan sulfate ligand binds to receptors which lead to the activation of the mitogenactivated protein (MAP) kinase pathway.  The cascade of events starts with the activation of the protein Ras, which then activates the protein Raf, a kinase that activates another kinase called MEK (Mitogen-activated, ERK-activating Kinase).  This phosphorylates ERK (Extracellular signal Regulated Kinase), which enters the nucleus and activates transcription factors by phosphorylation.  Ras is one of the most common mutations in human tumors.

 Developmental functions include early mesoderm and neural induction, anteroposterior patterning, brain regionalization, and promotion of limb outgrowth, angiogenesis, wound healing processes.  Human FGFR mutations are associated with several skeletal malformation syndromes, wherein skull, limb and rib cartilages fail to grow or differentiate.

3. Hedgehog family- polypeptides important in dorsoventral patterning of the neural tube and anteroposterior patterning of limbs (sonic hedgehog), skeletal development (Indian hedgehog), spermatogenesis (desert hedgehog is a Sertoli cell product that specifies lineage of fetal Leydig cells). The receptor is called patched, a constitutively active G-protein linked class. In the presence of hedgehog, patched is active and represses the activity of a membrane protein called smoothened, which in turn activates a Gli-type transcription factor which moves to the nucleus and turn on genes.

 Sonic hedgehog suppresses transcription of the TGFF and Wnt genes causing cell growth inhibition.  Mutation in the human homologue PATCHED (PTC) causes Gorlin syndrome, rib defects, cysts of the jaw and basal cell carcinoma.

 Holoprosencephaly, the failure to form cerebral hemispheres (1:16,000 live births; 1:200 spontaneous abortions) is linked to SHH and PTCH mutations.  Cyclopia, results if gestating mammals consume the pathway inhibitor cyclopamine.  Activation of the hedgehog pathway has been implicated in the development of cancers (brain, lung, mammary gland, prostrate, skin).  Biotech companies are attempting to turn this pathway ON after a patient has a stroke or heart attack, since the pathway provides a protective barrier against cell death and ischemia.

4. Wnt family- H2O insoluble single-chain polypeptides  Establish polarity of the limb for the dorso/vental axis, participate in brain, muscle, gonads and kidney development.  The Wnt receptors are called frizzleds, which when activated causes the expression of the glycogen synthase kinase (gsk3), via a multifunctional protein called dishevelled.  When active, dishevelled phosphorylates Fcatenin, a molecule involved in cell adhesion and gene regulation.  When gsk3 is repressed, F-catenin combines with the transcription factor Tcf-1, and conveys it into the nucleus.

5. Epidermal growth factor family (EGF)- polypeptides structurally similar to TGFE. EGF receptors also activate the MAP kinase pathway.

6.Ephrin system- operates between cells making contact with each other.  Involved in gastrulation, establishment of segmentation in the hindbrain, and topographic maps in the nervous system.  Ephrin receptors make up the largest subgroup of the receptor tyrosine kinase (RTK) family. The protein encoded by this gene binds to ephrin-B2 and plays an essential role in vascular development.

7. Delta-Notch system- the ligand Delta and receptor Notch are both are integral membrane proteins, which interact if cells making them are in contact.  Notch cleaves after binding, causing the release of a transcription factor CSL-/, which migrates to the nucleus and activates target genes.  The Notch receptor is implicated in lateral inhibition, a type of signaling of a dominant cell to its subservient neighbors.  Important in neurogenesis, & somitogenesis.  Mutations in human Notch receptors cause severe NS abnormalities.

8. Spatzle system- important in dorsoventral patterning of Drosophila. The receptor of this ligand Toll, is a homolog of the vertebrate interleukin1. Toll activates a kinase that phosphorylate the protein I/B, causing it to dissociate from NF/B. The latter is a transcription factor which turn on genes.

9. Leukemia Inhibitory Factors (LIF)include interleukin 6, oncostatin, and ciliary neurotrophic factor. Important in maintaining pluripotency in the mouse embryo, and induction of kidney tubules.  They bind to receptors which form a complex with a transmembrane glycoprotein gp130, associated with intracellular kinases called JAKs.  The active complex then phosphorylate STAT type transcription factors which activate target genes in the nucleus.

10.Neurotrophinsessential for neuron survival, and secreted by target cells to which which axons project.  Prototypes are the nerve growth factor (NGF), brain-derived neurotropic factors (BDNF), and neurotrophin 3 and 4.  Receptors are called Trk and p75. Diffusible factors include netrins and semaphorins.  NGF levels have been shown to be significantly elevated during the 1st year of a romantic relationship.  Alzheimer's disease, stroke, and cancer, may cause neural damage in part through the misfunction of neurotrophins.

Trk receptor-mediated signal transduction pathways

Binding of neurotrophins leads to the recruitment of proteins that interact with Trk receptors. These lead to the activation of signaling pathways (e.g., Ras, phosphatidylinositol-3-kinase, and phospholipase C pathways, and result in activation of gene expression, neuronal survival, and neurite outgrowth Adaptor proteins are red, kinase green, small G proteins blue, and transcription factors brown.

p75-mediated signal transduction pathways

P75NTR interacts with proteins, including TRAF6, RhoA, NRAGE (neurotrophin receptor-interacting MAGE homologue), SC-1, and NRIF, and regulates gene expression, the cell cycle, apoptosis, mitogenic responses, and growth cone motility. The Jun kinase pathway can be inhibited by activation of the Rasphosphatidylinositol-3-kinase pathway by Trk receptors. Adaptor proteins are red, kinase green, small G proteins blue, and transcription factors brown.

11.Insulin family- includes insulin and insulinlike growth factors. Important in growth control. Binding to receptors cause phosphorylation of adapter proteins which lead to the activation of protein kinases A & B.

 Mutations in genes that belong to the same transduction pathway can give similar results (genetic heterogeneity), e.g. Sonic hedgehog and cholesterol synthesis gene mutations can cause cyclopia.  On the other hand, the same mutation can produce a different phenotype in different individuals (phenotypic heterogeneity)  Example: FGF mutation can cause symptoms ranging from the flipper-like stump of phocomelia, to a mild abnormality of the thumb.  Small, soluble signals (MW 1500) pass through gap junction channels made of connexin proteins. Mutations in human connexins cause congenital malformations of the heart & ear.

 Growth factors regulate cell growth, proliferation, and survival.  These are all deregulated in cancer, resulting to: 1.Growth signal autonomy 2.Insensitivity to anti-growth signals 3.Resistance to apoptosis

CYTOSKELETON and DEVELOPMENT Regionalization of egg substances, e.g. localization of certain mRNAs Orientation of mitosis Cell movement, as individual cells, or part of moving cell sheets Changes in cell shape in response to an external signal.

CELL SURFACE MOLECULES

1. Cadherins- a family of single-pass transmembrane glycoproteins which stick embryonic cells together in the presence of calcium (E-cadherin are found in epithelial tissues, N-cadherin occurs in neural tissue). 2. Cell adhesion molecules (CAMs)- single-pass transmembrane glycoproteins which do not require calcium to bind to other cells. 3. Integrins- cell surface glycoproteins that require (Ca+2 or Mg+2), to interact with components of the extracellular matrix.

Extracellular Matrix (ECM) & Development

The matrix regulates the behavior of the cells that contact it, influencing their survival, development, migration, proliferation, shape, & function. The extent of cell spreading on a substratum, rather than the number of matrix molecules the cell contacts, influences cell survival

1. Glycosaminoglycans (GAGs)- constituents of proteoglycans, which have a protein core to which one or more GAG chains are added. 2. Collagens - polypeptides rich in proline and glycine. Cross-linking through their lysine residues contributes to the changing mechanical properties of tissues with age. 3. Elastin- a protein with extensive inter-molecular cross-linking, conferring elasticity on tissues in which it is abundant. 4. Fibronectin- large disulfide-bonded dimer polypeptides produced by alternative splicing. They are important in cell migration. 5. Laminin- composed of 3 polypeptide chains joined in a cross-shape. Abundant in the basal lamina, they promote cell adhesion and growth, changing cell shape, and permitting cell migration.

Feedback and Crosstalk: The activity of signaling pathways within the cell is regulated by feedback loops that control the extent and duration of signaling. Different signaling pathways also interact to regulate each others activity. Networks of Cellular Signal Transduction: The extensive crosstalk between individual pathways leads to the formation of complex signaling networks. A full understanding of signaling within the cell will require the development of quantitative network models.

http://www.sinauer.com/cooper/4e/animations1501.html http://www.sinauer.com/cooper/4e/animations1502.html http://www.sinauer.com/cooper/4e/animations1503.html http://www.wiley.com/college/boyer/0470003790/animati ons/signal_transduction/signal_transduction.html http://bcs.whfreeman.com/thelifewire/content/chp15/150 20.html http://www.whfreeman.com/kuby/content/anm/kb02an01 .html http://www.bio.davidson.edu/courses/Immunology/Flash/ MAPK.html