Mcm- Dev Bio

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Induction

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One group of cells changing the behavior of another group of cells

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Competence

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Actively acquiring the ability to respond to an inductive signal; responder tissue must be competent for it to be induced

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Reciprocal Interaction

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Once a tissue is induced, it may become an inducer and the original tissue induced

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Instructive Interaction

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Inducing signal is necessary for new gene expression to occur in the responder

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Permissive Interaction

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All necessary genes are expressed to proceed, but an environmental signal is needed to proceed

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Epithelial-mesenchymal Interactions

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Type of induction interaction, important for development of limbs, organs, and cutaneous structures.
* Epithelia- connected sheets of cells derived from any germ layer
* Mesenchyme- supporting cells, loosely packed connective tissues, mesodermal origin

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2 Properties of Epithelial-mesenchymal Interactions

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Regional specificity
Genetic specificity

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Juxtacrine Signaling

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Proteins on one cell surface interact with proteins on an adjacent cell surface

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Paracrine Signaling

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* Signaling proteins diffuse over a short distance to bind receptors on other cells
* The diffusible proteins are called growth differentiation factors (GDFs)

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Growth Differentiation Factors (GDFs)

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* Ligands that induce responses in neighboring cells
* These are that diffusible proteins used in paracrine signaling

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4 Major Families of Paracrine Signaling

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Fibroblast growth factors (FGFs)
Hedgehog family
Wnt family
TGF-β superfamily

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Fibroblast growth factors (FGFs)

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Paracrine signaling family, which contains over a dozen members.
Activate fibroblast growth factor receptors (FGFRs). For example, receptor tyrosine kinases, which are transmembrane with an extracellular ligand domain and intracellular kinase domain that phosphorylates proteins within responder.
Also function in angiogenesis, axon extension, and mesoderm formation.

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Hedgehog Family

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* Paracrine signaling family
* 3 members
* Induces cells types and borders
* Sonic hedgehog: most often used
- secreted protein
- neural tube patterning
- somite cartilage induction
- AP limb axes
- digestive tube differentiation

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Wnt Family

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* Paracrine signaling family
* 15 members
* Muscle induction in somites
* Polarity of limbs
* Urogenital system

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TGF-β Superfamily

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* Paracrine signaling family
* Peptides secreted as homo or heterodimers
* Regulate formation of the extracellular matrix between cells
* Regulate cell division
* Important in duct forming
* Include the bone morphogenic protein (BMP) family

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How are the signals between inducer and responder transmitted?

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* Juxtacrine signaling
* Paracrine signaling

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Bone Morphogenic Protein (BMP) Family

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* Part of the TGF-β Superfamily
* Regulate cell division, death, and migration
* Important in eye development
* Include proteins such as Nodal, which is responsible for left-right axis formation

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Signal Transduction Pathways

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* Pathway between the cell membrane and gene expression, which is activated via ligand-induced signaling at the cell membrane
* Conformational change from ligand binding activates transmembrane receptor activity, which catalyzes a cascade of reactions resulting in gene expression.

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5 Types of Signal Transduction Pathways in Development

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* Receptor-tyrosine kinase pathway
* Smad pathway
* JAK-STAT pathway
* Wnt pathway
* Hedgehog pathway

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Receptor-Tyrosine Kinase Pathway

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* Signal transduction pathway
* Ligands are FGFs and other growth factors
* Ligands induce dimers that are activated kinases
* This induces phosphorylation cascade, which activates latent transcription factor

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Smad Pathway

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* Signal transduction pathway
* Activated by TGF-β family
* TGF-β receptors dimerize and phosphorylate SMAD transcription factors
* The TGF-β superfamily ligand Nodal activates the Smad pathway in those cells responsible for the formation of the mesoderm and left-right axis

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JAK-STAT Pathway

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* Signal transduction pathway
* JAK receptors dimerize and phosphorylate STAT transcription factors, which dimerize
* Important in fetal bone growth
* Premature activation of this pathway can result in mutations of the gene encoding FGFR3, which normally signals chrondrocytes to stop dividing and differentiate into cartilage.
* Gain of function mutations in the FGFR3 gene result in dwarfism

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Wnt Pathway

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* Signal transduction pathway
* Frizzled family receptors
* Ligand binding inhibits APC complex proteins, which bind β-catenin
* β-catenin can enter the nucleus and become a transcription factor
* APC complex is a tumor suppressor and implicated in colon cancer

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Hedgehog Pathway

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* Signal transduction pathway
* Ligand binding to patched protein, which is an inhibitor of smoothened protein, alters the patched protein's shape so that it no longer inhibits smoothened.
* Smoothened protein then acts to prevent Ci protein from being cleaved (where it would then act as a transcription repressor)
* Intact Ci protein can now enter the nucleus and act as a transcription activator.
* Important in limb and neural differentiation

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Teratogens

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Environmental factors that cause developmental disease

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Notch

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* Juxtacrine signaling transmembrane protein that binds transmembrane proteins on an adjacent cell
* When activated, cleaved by proteases and become TF
* Delta and Notch signal cell to become neural
* Important in formation of optic neurons

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5 Families Involved in Juxtacrine Signaling During Development

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* Notch
* Fibronectin
* Lamin
* Integrins
* Connexins

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Fibronectin

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* Juxtacrine signaling extracellular matrix protein
* Important role in cell migration: pave the roads for migrating germ cells and heart cells

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Lamin

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* Juxtacrine signaling extracellular matrix protein
* Important in cell adhesion and growth

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Integrins

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* Juxtacrine signaling transmembrane protein
* Bind extracellular matrix and intracellular actin
* Allow cell movement through actin contraction
* Many cells require bound integrins to survive; they activate survival signaling

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Connexins

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* Juxtacrine signaling transmembrane protein
* Make up gap junctions (channels formed between adjacent cell membranes that allow small soluble molecules to diffuse freely)

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Cross-talk

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2 signaling pathways reinforce each other

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Hox genes

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* Determine AP polarity
* Arranged in the genome in the same order as they are expressed anteriorly (3') to posteriorly (5')
* 13 complexes with paralogous groups
* Expressed along the dorsal axis
* Determine limb bud formation
* Specify the proximal-distal axis along the limb
* Activated by retinoic acid
* Binds retinoic acid receptors (RAR)

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Apical Ectodermal Ridge

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* Thickened layer of ectodermal cells at the distal tip of a developing limb bud
* Becomes the major signaling center for all limb axes during development
* Responders: Ectoderm; Inducers: Invading mesenchyme (FGFs)

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Thalidomide

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* Teratogen that causes phocomelia ("seal limb")
* Prescribed in the 1950s to pregnant women to combat morning sickness
* Banned in 1962
* Mechanism still not well known: DNA intercalating agent, metabolites, antiangiogenic and anti-inflammatory
* Effective in treating leprosy and some cancers