Chapter 3 & Part 2 (Lecture 5&6).pdf

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Cell and Systems Biology
Ashley Bruce

Chapter 3 continued Juxtacrine Signaling and Cell Patterning  Induction occur on the cell-to-cell level  In the formation of the vulva in the nematode worm Caenorhabditis elegans, an epidermal growth factor-like inducer activates the RTK pathway Vulval induction in C. elegans  Most individuals are hermaphrodites  Early development, they are male -> gonads produce sperm which is stored for later use  As they grow older, they develop ovaries  The eggs “roll” through the region of sperm storage, fertilized inside the nematode, and pass out of the body through the vulva  One inductive signal generates a variety of cell types  The vulva forms during the larval stage from 6 cells called the vulval precursor cells (VPCs)  The cell connecting the overlying gonad to the vulval precursor cells -> anchor cell  This cell secretes LIN-3 protein, a paracrine factor that activates the RTK pathway o If the anchor cell is destroyed, the VPCs will not form a vulva o Instead, it will become part of the hypodermis (skin)  The 6 VPCs form an equivalence group o Each member is competent to become induced by the anchor cell o Can assume any of 3 fates, depending on its proximity to the anchor cell  Directly beneath the anchor cell: divides to form the central vulval cells  The 2 cells flanking that central: divide to become the lateral vulval cells  3 cells farther away: generate hypodermal cell o If the 3 central VPCs are destroyed, the 3 outer cells generate vulval cells instead The ECM as a Source of Developmental Signals  ECM: an insoluble network consisting of macromolecules secreted by cells into their immediate environment  These macromolecules form a region of noncellular material In the interstices between the cells  ECM is a critical region for much of animal development  Cell adhesion, migration, and the formation of epithelial sheets and tubes all depend on the ability of cells to form attachments to ECMs o In the formation of epithelia, these attachments have to be extremely strong o Migration, attachments have to be made, broken, and made again o ECM merely serves as a permissive substrate to which cells can adhere, or on which they can migrate o Provides the directions for cell movement or the signal for a developmental event o ECM are made of collagen, proteoglycans, and a variety of specialized glycoprotein molecules  Proteoglycans play critically important roles in the delivery of the paracrine factors o Consist of core proteins with covalently attached glycosaminoglycan polysaccharide side chains o 2 of the most widespread proteoglycans: heparan sulfate and chondroitan sulfate  Large glycoproteins are responsible for organizing the matrix and the cells into an ordered structure o Fibronectin: very large glycoprotein dimer synthesizedby numerous cell types  One function of Fn: serve as a general adhesive molecule, linking cells to one another and to other substrates (collagen and proteoglycans)  Has several distinct binding sites  Interaction with the appropriate molecules results in the proper alignment of cells with the ECM  Also has an important role in cell migration since the “roads” are paved with this protein  Laminin and type IV collagen are major components of a type of ECM called the basal lamina o BL is characterized by closely knit sheets that surround epithelial tissue o The adhesion of epithelial cells to laminin is much greater than the affinity of mesenchymal cells for Fn o Laminin plays a role in assembling the ECM, promoting cell adhesion and growth, changing cell shape, and permitting cell migration Integrins: Receptors for ECM molecules  integrins: main Fn receptors, extremely large protein that could bind Fn on the outside of the cell, span the membrane, and bind cytoskeletal proteins on the inside of the cell  Thus it unites the extracellular and intracellular matrices  On the extracellular side, integrins bind to the aa sequence RGD, found in several ECM adhesive proteins  On the cytoplasmic side, integrins bind to talin, and α-actinin, which connect to actin microfilaments  This dual binding enables the cell to move by contracting the actin microfilaments against the fixed ECM  Integrins can also signal from the outside of the cell to the inside, altering gene expression  Integrin is critical for inducing specific gene expressionin developing tissues  The presence of bound integrin prevents the activation of genes that promote apoptosis  Some of the genes induced by matrix attachment are being identified o When plated onto tissue culture plastic, mouse mammary gland cells will divide o Indeed, genes for cell division are expressed, while genes for differentiated products of the mammary gland are not expressed o If the same cells are plated onto plastic coated with BL, the cells stop dividing and the genes of differentiated mammary gland cells are expressed  This happens only after the integrins of the mammary gland cells bind to the laminin of the BL o Then the gene for lactoferrin is expressing and the gene for p21, a cell division inhibitor o C-myc and cyclinD1 genes become silent o Eventually, all the genes are expressed and the cell division genes remain turned off o By this time, the mgc have enveloped themselvesin a basal lamina, forming a secretory epithelium o The binding of integrins to laminin is essential for transcription of the casein gene, and the integrins act in concert with prolactin to activate that gene’s expression  Several studies have shown that the binding of integrins to an ECM can stimulate the RTK pathway The Epithelial-Mesenchumal Transition  Epithelial-mesenchymal transition (EMT), integrates all the processes discussed in this chapter  EMT: orderly series of events whereby epithelial cells are transformed into mesenchymal cells  A polarized stationary epithelial cell, which normally interacts with BL through its basal surface, becomes a migratory mesenchymal cell that can invade tissues and form organs in new places  Usually initiated when paracrine factors from neighbouring cells activate gene expression in the target cells, instructing the target cells to: o downregulate their cadherins, o release their attachment to laming and other BL components, o rearrange their actin cytoskeleton, o and secrete new ECM molecules characteristic of mesenchymal cells  EMT is critical during development: 1. The formation of neural crest cells from the dorsalmost region of the neural tube 2. The formation of mesoderm in chick embryos, wherein cells that had been part of an epithelial layer become mesodermal and migrate into the embryo 3. The formation of vertebrae precursor cells from the somites, wherein these cells detach from the somite and migrate around the developing spinal cord  EMT is also important in adults, in whom it is needed for wound healing  The most critical adult form of EMT: cancer metastasis -> cells that have been part of a solid tumour mass leave that tumour to invade other tissues and form secondary tumours elsewhere in the body o In metastasis, the processes that generated the cellular transition in the embryo are reactivated, allowing cancer cells to migrate and become invasive The Cell Biology of Paracrine Signaling  Paracrine factors can rearrange the cell surface, and the cell surface is critical in regulating paracrine factor synthesis, flow, and function  The actions of paracrine signals often change the composition of the cell membrane  Endosomal signaling in the WNT pathway o When Wnt binds to its receptors, the β- catenin destruction complex binds to the receptor, and the entire complex is internalized into the cell in membrane- bound vesicles called endosomes o This enables the survival of β-catenin o This process appears to be critical for the accumulation of β-catenin , and proteins that aid in this endocytosis  Diffusion of paracrine factors o Paracrine factors do not flow freely through the ECM o Wnt paracrine factor diffusion is affected by other proteins a. Diffusion of Wg is enhanced by Swim, a protein that stabilized Wg and that is made by some of the wing cells. When Swim is not present (mutant), Wg does not disperse but is confined to the narrow band of Wg-expressing cells b. Wg usually activates the distal-less gene in much of the WT wing. In Swim mutatns, the range of Distal-less expression is confined to those areas near the band of Wg-expressing cells o The factor can be bound by the cell membranes and ECM of the tissues o In some cases, such binding can impede the spread of a paracrine morphogen and even target the paracrine factor for degradation o Wnt proteins do not diffuse far from the cells secreting them unless helped by other proteins  Thus, the range of Wnt factors is significantly extended when the nearby cells secrete proteins that bind to the paracrine factor and prevent it from binding prematurely to the target tissue o Target tissue can promote diffusion, retard diffusion, or degrade the paracrine factor  Cilia and lamellipodia as signal reception centers o In many cases, the reception of paracrine factors is not uniform throughout the cell membrane o In tunicates, an asymmetric division of a pre-cardiac founder cell gives rise to the heart progenitors  Although both daughter cells are exposed to the inductive signal Fgf9, only the smaller of the 2 responds to generate the heart progenitor lineage  During asymmetric division, localized protrusions (lamellipodia) form on the anterior ventral side of the founder cell  These protrusions are actin-rich and result from the polarized localization of a Rho GTPase in this region  It is possible that the underlying ECM of the ventral epidermis stimulates this localization  At the same time, FGF receptor activity becomes concentrated in these protrusions  When the cell divides, the smaller daughter inherits these localized, activated FGF receptors, leading to differential activation of the genes that will form heart muscle  It is possible that, in the case of both the Hedgehog-receiving cilia and the FGF-receiving lamellipodia, the paracrine factor receptors become clustered to a high density and that the signal transducing proteins are brought into contact with each other Part Two: Specification – Introducing Cell Commitment and Early Embryonic Development  How are certain genes activated and repressed in one group of cells to turn them into mesoderm while a different set of genes is regulated to instruct cells to become endoderm?  Are there any principles or strategies that characterize the origins of different cell types? Levels of Commitment  Differentiation: the generation of specialized cell types  Last, overt stage in a series of events that commit a particular blastomere to become a particular cell type  Commitment: the cell might not look differentiated, but its developmental fate has become restricted  The process of commitment can be divided into 2 stages: 1. Specification: labile phase; the fate of a cell or
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