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BIO230 Finals.pdf

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How do cells and tissues organize themselves spatially? Lecture 1: Membrane trafficking  Basic Principles of the Biosynthetic-Secretory and Endocytic Pathways o Polarized trafficking routes (proteins travel directly from one place to next)  Constitutive secretary  Start at the same place, materials being continuously budding off from the vesicle  Regulated secretary pathway  The vesicles are regulated, the cells tells the vesicle when to budding off o Sorting stations (bus stations of the cells) o Retrieval mechanism and general balance among routes (buses need to route around)  The concentration of cargo increases as it being budding off o Polarized transport route with the retrieval route  Some components are taken back to the Golgi.  Endocytosis o Cells collect resources by endocytosis (e.g. cholesterol)  Cholesterol in the fluid outside the cell is bound to LDL, cells have LDL receptors. Once grabbed on, placed into endocytosis pits and get internalized inside the cell, it targets to the sorting station. (receptors are recycled, but the cholesterol are targeted to the lysosome) o Cells down regulate cell surface signaling by endocytosis  The cell can pull the entire receptor complex inside the cell, after endocytosis, thru specific soring; it can be converted to a multi-vesicular body. And the vesicle inside the vesicle is targeted by lysosome.  Local membrane changes occur during this trafficking o Fusionvesicles fusing with the membrane  SNAREs  v-SNAREs and t-SNAREs bring the two membranes together. Forced the membrane so close so there’s no water in between. o Invaginationmembrane bending in, towards the cytosol.  Clathrin & Dyamin  Clatherin forms a rounded coat, this drives the vesicles inward.  Dynamin curl around the neck of the protein, forces them, exclude the water, and promote the cells separate. Act similar to SNAREs.  COPI and COPII o Budding moving from one cytoplasmic space to another  ESCRT complex  Push the local plasma membrane outwards and then pinch it off to release the virus outside the cell.  Membrane invagination, fusion and budding events occur at specific sites in the system to control polarized trafficking and retrieval  Control of specificity in polarized trafficking o Inositol phospholipids  inositol sugar head group can be phosphorylated at the hydroxyl group  Kinase add phosphate group  Phosphatasesremove phosphate group  Each phosphoinositide species binds to specific proteins o Rab GTPase  GEFexchange GDP to GTP  GAPexchange GTP to GDP  Rab11recycling endosomes  Rab5Aplasma membrane, clathrin-coated vesicles, early endosomes  Rab7 late endosomes  Rabs are recruited to specific membranes by RabGEFs, their activation promotes downstream effects Lecture 2: Cytoskeletal networks  Microtubules (SubunitProtofilamentnetwork) o Each protofilament is made up of β-tubulin, α-tubulin o γ-tubulin, complexes nucleate microtubules  Minus end connect γ -tubulin, and the plus end grow outside  cap of GTP-bound tubulin o Forms like a tubes, 13 filaments, dynamic instability o Coordinate system  A purified centrosome was mixed with purified tubulin subunits in an artificial membrane-bound container. It moves to the centre of the container as microtubule plus ends push on the outer membraneminus ends central/plus ends outwards  Motor move cargo through the microtubule networks o Dyneinminus end directed (move towards centre) o Kinesinplus end directed (move outside) o The microtubule network is very dynamic and can be reorganized  The actin cytoskeleton is inherently polarized (Subunitfilamentsnetwork) o Monomers, binds to ATP, there are enzymes hydrolysis ATP when it enters the filaments. o Asymmetric (structurally different). Forming helical structure, head to tail. o Polarized assembly and disassembly leads to treadmilling  Treadmilling actin networks need traction to drive cells forward  A stationary anchor binds one part of the filament. o The ARP complex nucleates actin filaments and branches actin filaments to form polarized 2-D networks.  In animals, cells migrate on (and through) the extracellular matrix, a non-cellular material made of proteins and polysaccharide o Integrins connect the actin cytoskeleton to extracellular matrix molecules  Subunits of integrins liked to the actin cytoskeleton via adaptor proteins. o Chemoattractant receptors orient the actin networks  Extracellular signal control the behavior of the cell. Chasing the cells, the bacterium emits small molecule, and host (immune cells) has receptors to recognize them. A gradient of chemotractin created, activated the receptors. Activated the ARP complex. turn on the actin polymerization  Actin networks can undergo other large scale rearrangements o Localized assembly of the contractile ring that divides daughter cells after mitosis. Lecture 3: Cell adhesion  Cells are organized into one of two main tissue categories o Epithelial tissuedirect connected with minimal extracellular matrix beneath  More than 60% of the cell types in the vertebrate body are epithelial.  Lumen of gut  Skin o Connective tissuedispersed with extracellular matrix providing overall structure  Junction complexes o From apical to basal  Tight junctionadherens junctiondesmosomegap junction   Adherens junction structure o Adherines junctions form strong continuous adhesion belts o Cadherin clusters mediate the adhesion  Hemophiliac interaction between cadherin receptors  Links to actin cytoskeleton o Tissue maintenance during development  Sheet of cells flowing around, they can adhere together and also allow rearrangement to occur o Tumour suppression  The loss of epithelial structure is a hallmark of cancer  Cadherins are tumour suppressors  Tight junctions enclose the apical end of each cell in an epithelial sheet o Claudin  4-pass transmembrane protein  Tight junction formation, assembles the structure but leaky o Occludin  4-pass transmembrane receptor  Required for barrier function  Importance of epithelial structure o Epithelial polarity controls solute diffusion between our body compartments  Cell Polarity is Fundamental to Cell and Developmental Biology o “landmark”  Sperm entry provides the landmark of the cell, cue to break symmetry, the flow of cytoskeleton from the cell.  Different anterior posterior cues, different side of the cell determines different functions of the cell, one side destined to become one sets of organs o Adherens junctions (AJs) are important landmarks for epithelial polarity  Mesenchymal-to-epithelial transition  More polarities form downstream of it, cue apical cues. Mutually antagonist relationship with the basal lateral domains How do multicellular organisms develop? Lecture 4: Tissue morphogenesis  Skin epithelia o Surface cells are continuously flakes off, and replaces.  Gut epithelia  Mammary gland epithelia o Mammary gland develops alveoli; these ducts are simple epithelial sacs.  Embryogenesis o Begin with blastocyst (simple, hollow cell). o Trophectoderm: outside, not embryonic, supply tissue for placenta  Internalization of cells o Gastrulation  Sea urchin  Ectodermepidermis/nervous system (outside)  Mesodermmuscles/connective tissue/blood vessels (middle)  Endodermgut/lung/liver (inside)  Mechanisms of cell internalization o Ingression/delamination  Epithelial-to-mesenchymal transitions the epithelium are breaking off and migrating inside,  Epithelial-to-mesenchymal transitions are tightly regulated during normal developmentQuail/chick cells o Invagination/involution  Polarity direct actin and myosin to the top. Constrict the top of the cellSeries of rectangular cells becoming more pyramidal. Bend the whole tissue  Neural tube development  ventral expression of a transcription factor called Twist specifies the cells to undergo mesoderm internalization in Drosophila Elongation of the embryo  Mechanisms of embryo elongation o Convergent extension  Xenopus embryogenesis  Cells converging toward the midline, as the cells converging. The overall structure is extended. o Cell division and cell shape change  Arabidopsis embryogenesis  At the tip of the root, there is a zone of cell division, dividing rapidly, there are nowhere the daughter cells forms, and it will be forced outward.  The orientation of cell elongation is regulated by the orientation of cellulose microfibrils and driven by driven by turgor pressure  Elongation of gut villi  Fine repositioning of cells o Cell sorting  Germ cell layers  Take three early germ layer, and randomly mix them. Leave them they will sort out back.  Differential cadherin expression and cell sorting and the patterning of the brain  The homophilic adhesion between cadherins may group specific cells together o Directed cell migration  Cell migration in the cerebral cortex  Axon pathfinding  The neuron migrates to the midline, and move in a highway to the brain thru floor plate. Creating the spinal cord. o The growth cone at the tip of the axon. Similar to immune cell chasing bacterium. Secretion of chemical from the midline, where the embryo is directing the cell to go. Forming a gradient, growth cone has receptors to receive signal, forming actin framework of chemical from the midline. Lecture 5: Tissue patterning  Intrinsic change o Asymmetric cell division  Sister cells are born different, a polarity is gained. When this cell divide, one cell gains material different from the other cell.  Requires cortical polarity & proper spindle alignment  Extrinsic signaling o Direct lateral inhibition  Lateral inhibition by Notch signaling  Mechanisms involve interaction between 2 trans-membrane proteins, one being the ligand (Delta). They are both connected to plasma membrane, hence local interaction. Only cell in direct contact can be affect. Start with low differentiated state. The ligand Delta binds to Notch receptors, this inhibit the cell from differentiating, also inhibits the inhibitory signal being sent back to the other cell. Both protein in expressed. Low level inhibition across the field.  When one of the gain an advantage (increase slightly activity). Sent a stronger signal, it will shut down the inhibitory signal, inhibited the inhibitory signal, and it gets even stronger. It goes thru this cycle until it completely shut off. o Induction by diffusible signals  Morphogens and organizers  Secreted molecules are called morphogens. The morphogens concentrations dictate cell fate. you can have the same molecules, but with different gradients, high gradients will have a different pattern with low gradients o Organizer function in vertebrate limb development  Mechanism is control by the polarizing organizer region. The source of the morphogen is called sonic hedgehog (Shh). The expression of the gene is expressed and spread as a gradient. o “Organizer” tissues act as morphogen sources  Regulatory hierarchies o Regulatory hierarchies refine patterns of cell differentiation to create segmental pattern  Gap gene: Kruppel  Segment-polarity gene: Gooseberry  HOX genesSpecifies which part develops into what. o “Antennapedia” (Antp)  the mutated gene cause legs to growing in the position of the antenna o Order of the gene position on the chromosome is the same order they are expressed on the animal body. o Hox genes encode transcription factors with different targets in different species.  Drosophila vs. Dragon fly Lecture 6: Stem cells  Molecular turnover o auditory hair cells  Vibration in the fluid pushes the tectorial membrane, this pushes the top of the sensory cells, they have the projections called stereocilia, then tectorial membrane push on them, and they bend. Sound causes the sterocilia to tilt. When they tilt, this affect one tether, cadherin adhesion molecules undergoes hemophilic cell-to-cell adhesion. cadherin pull on the lid of the channel, and opens the lid of the channel, this allow ions to flow, induced action potentials, then the AP travels thru the neuron  Stereocilia are filled and supported by actin, the actin undergoes continually polarized treadmilling. o photoreceptor cells  The photoreceptors are at the back of the eye, connecting to nerve cells. Converts photons to nerve impulses.  Pulse-chase experiment  Cell exposed to radio-labeled leucine for a short time period of time. Radioactivity that can be detected, because it's leucine, so it can incorporated into protein. By monitoring the radio activity, it will either be detect in the cell for a lifetime, or it will be lost gradually. o Extracellular example of molecular turnover: bone  Osteoclastcontinuously eating the bone away  Osteoblastforming bones  Cellular turnover o Stem cell dependent  Divisional asymmetry  One daughter receives factors promoting “stemness”, and the other receives factors promoting differentiation o Problemif stem cells are lost, their original numbers cannot be restored  Environmental asymmetry  The daughter's fate is dependent by the environment they are born into. One received the environment signal to maintain stemness. The other is actually pushed to another environment, received signal promote terminal differentiation. o Can lose stem cells, and remain them in the stem cell environment, to have the daughter cell to be stem cells again  Stem cells divide slowly o Because:  Cell division can create mutation  Telomere depletion associated with cell division o Therefore, transit amplifying cells expand cell numbers before final differentiation, they expand their numbers before they differentiated, so even when stem cells divide slowly, they can divide rapidly  skin cells o basal lamina provides a niche for the stem cells  After detaching from the basal lamina, the cells differentiate through a linear sequence of cell types and are finally shed from the animal  Gut cells.  blood cells o Blood stem cells differentiate into various populations creating a branched pathway to final differentiation o Blood stem cells and their progeny reside in bone marrow  Homogenize mouse bone are expose to fluorescent antibodies recognizing specific cell surface molecule, then the labelled cells are isolated by Fluorescence-Activated Cell Sorting (FACS) o Blood stem cells are maintained through interactions with stromal cells in the bone marrow (osteoblast)  Stem cell independent o liver cells and insulin-secreting cells of the pancreas  Medical uses for stem cells o Embryonic stem (ES) cells can proliferate indefinitely in culture and have full developmental potential  Take cells from early embryo, cultured them and add mimicry signals to make them grow into different cells  This can increase the yield of cells needed for treatments, but ethical issues, immune rejection and the potential of cancer are still concerns o Two potential ways to avoid immune rejection of ES cells  Somatic cell nuclear transfer: use a nucleus from one of the patient’s own cells and transfer it into an unfertilized egg to develop an embryo from which ES cells can be harvested  Treat some of the patient’s own cells with factor known to specify ES cell character (e.g. a combination of Oct3/4, Sox2, Myc and Klf4 can convert differentiated cells into cells with ES cell characteristics) How do cells communicate with each other? Lecture 7: Principles of cellular signalling  Examples of unicellular communication o Quorum sensing in bacteria  Many bacterial cells can emit signals into the extracellular space, coordinates motility, production of antibiotics, sexual relations. o Mating in budding yeast o Aggregation of ameboid cells  aggregate together when no food available, form a fruiting body, and move to a place with food  The basics of sending and receiving signals o Signaling occurs over short or long distances  Contact-dependent signaling  signals are retained on the cell surface (Notch-Delta signalling)  Paracrine signaling  Molecules diffuse away to surrounding cells, but only diffuse in a short distance o Signaling occurs over short or long distances  Synaptic signaling  Neurons extend ax
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