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Cell biology and cellular processes
Systems biology for system engineers Part 3 Sofia Pe(ersson
Informa9on Coding Dept. of Electrical Engineering
Linköping University
From genes to func9on
Figure 8-3 Essential Cell Biology (© Garland Science 2010)
BIOLOGY OF ANIMAL CELLS
Cell biology
Protein sor:ng and modifica:on Energy produc:on
Expresssion of lipids
RNA transla:on Molecule breakdown
Cytoskeletal anchorage
Cell biology For the purpose of this seminar we will highlight the mitochondrion, the cell membrane and the cytoskeleton.
Mitochondria Mitochondria are some9mes referred to as “power plants” as they generate adenosine triphosphate (ATP). They contain mitochondrial DNA (16 kilobases) that encodes genes for proteins and RNA (tRNA and rRNA).
wikipedia.org
The cell membrane Lipid bilayer
– Fluid mosaic model – Mobility in the plane, but not
across the membrane – Ac9ve transport required for
charged, large molecules Transmembrane proteins
– Channels – Cadherins and integrins
(cell contact) – Ligands and receptors
(cell signaling)
fsu.org
The cytoskeleton The cytoskeleton provides the cell with structural integrity, enables cell movement (migra9on) as well as molecular transport within the cell. The cytoskeleton is maintained by a balance of assembly and disassembly of its three types of protein filaments.
Mechanical strength
Intracellular transport Cellular movement and stress/contrac:on
Microtubules
Figure 17-17 Essential Cell Biology (© Garland Science 2010)
The microtubules enable transport from the nucleus to the cytoplasm via motor proteins (kinesins and dyneins) and are crucial during cell division.
Cellular transport
Essential Cell Biology (© Garland Science 2010)
Ac9n filament
Figure 17-32 Essential Cell Biology (© Garland Science 2010)
The ac7n filaments are thin and flexible, underlie the cell membrane, and are essen9al for cell morphology and migra9on.
Cell migra9on
Essential Cell Biology (© Garland Science 2010)
CELL DIVISION
Cell division Cell division does not only occur during development – cells replicate con9nuously. The rate varies between cell types and species and is affected by environmental changes.
Table 18-1 Essential Cell Biology (© Garland Science 2010)
The cell cycle The different phases of the cell division program are specified in the cell cycle. The G0 phase is a res9ng phase and can be considered as an extension of the G1 phase, or as a quiescent state.
Cell cycle checkpoints
Figure 18-3 Essential Cell Biology (© Garland Science 2010)
The cell passes a checkpoint before entering the next phase of the cell cycle.
DNA replica9on The helicase molecule unwinds the DNA-‐helix into two strands. The two strands are then copied by DNA polymerase – one con9nuously (leading strand) and the other in segments (lagging strand).
Essential Cell Biology (© Garland Science 2010)
Chromosome segrega9on
Figure 18-20 Essential Cell Biology (© Garland Science 2010)
The duplicated chromosomes are pulled apart during mitosis (nuclear and cytoplasmic separa9on) by the microtubules of the cytoskeleton.
Mitosis
Cell division
Essential Cell Biology (© Garland Science 2010)
CELL CONTACTS
Cell contacts Most animal cells are contact-‐dependent – a single cell in
suspension will die. How cells form contacts with their surroundings depends on the
extracellular environment.
The extracellular environment
Figure 20-10 Essential Cell Biology (© Garland Science 2010)
In adult 9ssues and organs, cells are surrounded by extracellular matrix (ECM) proteins, inters99al fluid and other cells. The ECM contains 9ssue-‐specific collagens and proteoglycans.
The extracellular environment
wormclassroom.org
During development, cells are surrounded by other cells and can, depending on species, come in contact with various substrates such as an egg shell. In later stages, ECM will be present as cells begin synthesis.
Cell–ECM contacts
Figure 20-14 Essential Cell Biology (© Garland Science 2010)
Cells adhere to the ECM via cell adhesion molecules (fibronec9n, vitronec9n, laminin etc.) that contain binding sites for both cell and ECM proteins. The transmembrane integrin molecules connect the cell adhesion molecules to the cytoskeleton.
Cell–cell contacts
Figure 20-24 Essential Cell Biology (© Garland Science 2010)
Cells adhere to other cells via transmembrane cadherin molecules, that are connected to the cytoskeleton via linker proteins.
Other cell-‐cell junc9ons
Figure 20-22 Essential Cell Biology (© Garland Science 2010)
Though cadherin contacts are the most common (especially during development) there are several types of cell–cell junc9ons.
CELL SIGNALING
Cell signaling
Figure 20-22 Essential Cell Biology (© Garland Science 2010)
There are several ways that cells communicate with each other
Receptors
Figure 16-8 Essential Cell Biology (© Garland Science 2010)
Receptors are proteins that bind specific molecules, ligands, according to a lock-‐and-‐key mechanism. They can be membrane-‐bound or intracellular.
External signaling
Figure 16-3 Essential Cell Biology (© Garland Science 2010)
Signals origina9ng from the extracellular environment. Communica9ons range from long-‐range influences to direct cell–cell interac9ons where both receptors and ligands are membrane-‐bound.
Downstream effect of signal
Figure 16-7 Essential Cell Biology (© Garland Science 2010)
An external signaling event can either cause a transcrip9onal event OR cause an altered protein func9on without transcrip9on (cytoskeletal remodeling).
Biomechanical cues Not only biochemical signaling events affect cellular behavior – cells react to their surroundings in other ways.
Inside-‐out
HI SUBSTRATE STIFFNESS LOW
Flat morphology Stress fibers
Less focal adhesions Substrate deforma:on
Cells contract and pull on their substrates, sensing their surroundings (other cells, the ECM etc) and prestressing the cell through the cytoskeleton.
Outside-‐in Cells respond to external mechanical cues – compression, shear, tension and hydrosta9c pressure – by altering their morphology and/or gene ac9vity Some adult 9ssues depend on this type of signaling (bone, car9lage, blood vessels etc.)
Compression
Shear
Hydrosta:c Pressure
Shear
Mechanotransduc9on
Holle et al., Curr Op Biotechnology (2011)
Inside-‐out
Engler et al., Cell (2006)
The s9ffness of a substrate controls cell adhesion and morphology.
Inside-‐out The s9ffness of a substrate is sufficient to induce differen9a9on in adult stem cells (MSCs).
Engler et al., Cell (2006)
Molecular strain gauges
Molecular strain gauges
Holle et al., Curr Op Biotechnology (2011)
Organizing the organism Each cell needs to be in the right place in the adult organism. During gastrula7on, cells are reposi9oned. For C. elegans, the E cells (making up the intes9ne) are transported into the central parts of the embryo.
wormbook.org
Organizing the organism Each cell needs to be in the right place in the adult organism. During gastrula7on, cells are reposi9oned. For C. elegans, the E cells (making up the intes9ne) are transported into the central parts of the embryo. This is achieved by cytoskeletal remodeling.
wormbook.org
Cell sor9ng
Lecuit et al., Nat Rev Mol Cell Biol (2007)
Cells organize into subpopula9ons that will reform even if the cells are mixed. There are two hypothesis as to why: The differen7al adhesion hypothesis Cells sort with neighbors that express a similar cadherin pabern. Surface tension hypothesis Cells sort with neighbors that have similar mechanical proper9es.
SYMMETRY-‐BREAKING IN CELL LINEAGES
Symmetry-‐breaking in cell lineages
Figure 8-19 Essential Cell Biology (© Garland Science 2010)
Two main mechanisms for symmetry breaking ü External signaling ü Asymmetric cell division
Through these events, various pathways are turned ON or OFF in the different cells (and subsequent lineages).
External signaling events
wkipedia.org
Transcrip9onal ac9va9on through a conforma9onal change of an intracellular protein domain that moves into the cell nucleus. The Notch pathway is highly conserved and shared among species.
Notch signaling in lineages
wormbook.org
In C. elegans, Notch signaling events establish differences between sibling cells throughout development.
Cell contact maps
Hench et al., Dev Biol (2009)
Notch signaling events require direct cell–cell contacts, but cell membrane posi9ons are difficult to determine.
Asymmetric divisions A cell polarizes its content (i.e. transcrip9on factors) prior to division, giving
rise to two dis9nct daughters. The polariza9on is established by par99oning proteins and complex cor9cal flows (ac9n filaments).
University of Washington (celldynamics.org)
Asymmetric cell division
wormbook.org
Asymmetric division in cell lineages
Hunter et al, Cell (1996)
By separa9ng transcrip9on factors and/or their repressors through asymmetric division, different cell fate programs are ini9ated in embryonic cells.
From genes to func9on
Transcrip9on Transla9on
Ac9va9on Capping, splicing and export Transport
What ini9ates and affects transcrip9on? ü Intracellular cell fate program ü Biochemical cues from the surrounding ü Mechanical cues from the surrounding
?
Context
Figure 16-6 Essential Cell Biology (© Garland Science 2010)
Animal cells require mul9ple extracellular signals. The cell fate is determined by the intrinsic ability to respond to a signal (not all cells express the same receptors) and the sum of all signals.
1. Introduc:on (Robert Forchheimer, March 28) • The biological cell, the gene9c code, cell lineages. Terminology
2. From genes to func:ons (Sofia Pebersson, April 4) • Gene regula9on and transcrip9on
3. Cell biology (Sofia Pebersson, April 11) • Cellular processes
4. Synthe:c biology (invited speaker Erik Gullberg, Uppsala University, April 18) • IGEM-‐2011/Team Uppsala
5. Models for cell and organism development (Jan-‐Åke Larsson, April 25) • ODE-‐ and PDE-‐models. Boolean models
6. Case study (Invited speaker Thomas Bürglin, Karolinska Ins9tute, Huddinge, May 16) • C. elegans
7. Organism morphology and 3D-‐modeling (Lena Klasén, May 23) • 3D-‐modeling of cells and cell popula9ons
ü ü ü
The seminar series