Developmental Mechanism - Apoptosis
This single term "apoptosis" describes the way in which the majority of cells die within our adult body are removed every day, "Programmed Cell Death". In development, apoptosis begins in the early blastocyst and is a developmental mechanism found throughout tissues in the embryo and fetus developmental stages. In addition to the many developmental roles this process is used in multicellular organisms to remove cells that are: aged, superfluous, infected, contain genetic errors or are transformed.
While the cellular morphological changes associated with this process are the same in all cells, there are many different signaling pathways that can "trigger" this process. They fall generally into two signalling classes either intrinsic or extrinsic to the cell. To describe "programmed cell death" as apoptosis was originally used in 1972 by Kerr, Wyllie and Currie.
- Mechanism Links: Epithelial Invagination | Epithelial Mesenchymal Transition | Epithelial Mesenchymal Interaction | Morphodynamics | Tube Formation | Apoptosis | Molecular | Cell Biology Lecture - Cell Death
Some Recent Findings
| Removing cells from the developing inner cell mass.
Cell death in bovine blastocyst
| Removing cells between digits (fingers and toes) of the upper and lower limbs.
Interdigital apoptosis in the mous hindlimb.
During ossification removing chondrocytes.
- Links: Bone Development
Removing excess or inappropriately connected neurons.
- Links: Neural
Removing excess primordial follicles from the ovary cortex.
- Links: Ovary Development
- Links: Mammary Gland
The overview diagram above shows the fate of each individual cell in the developing c. elegans.
- the "X" indicates cells that die by apoptosis during development.
- Zygote (P0 cell) divides into two daughter cells (AB and P1 cells).
- These two daughter cells then divide into the next generation.
Note the above image is not at a readable resolution, to view see large readable version (10,389 × 1,336 pixels). Embryonic cell lineage developed by J .E. Sulston, E. Schierenberg, J. G. White, J. N. Thomson.
Nobel Prize 2002
The 2002 Nobel Prize in Physiology or Medicine went to three researchers who originally identified this mechanism in the genetic regulation of organ development and programmed cell death.
- Sydney Brenner (b 1927), Berkeley, CA, USA, established C. elegans as a novel experimental model organism. This provided a unique opportunity to link genetic analysis to cell division, differentiation and organ development – and to follow these processes under the microscope. Brenner's discoveries, carried out in Cambridge, UK, laid the foundation for this year's Prize.
- John Sulston (b 1942), Cambridge, England, mapped a cell lineage where every cell division and differentiation could be followed in the development of a tissue in C. elegans. He showed that specific cells undergo programmed cell death as an integral part of the normal differentiation process, and he identified the first mutation of a gene participating in the cell death process.
- Robert Horvitz (b 1947), Cambridge, MA, USA, has discovered and characterized key genes controlling cell death in C. elegans. He has shown how these genes interact with each other in the cell death process and that corresponding genes exist in humans.
- Links: Nobel Prize 2002
Apoptotic Cell Morphology
The following cellular changes occur in sequence during apoptosis.
- loss of cell membrane phospholipid asymmetry
- Condensation of chromatin
- Reduction in nuclear size JCB - Nucleus changes
- Internucleosomal DNA cleavage TUNEL staining
- DNA ladder
- shrinkage of the cell
- Cleavage of cytoskeletal proteins PNAS - Actin cleavage by ICE-like proteases
- note actin also binds DNase 1, cleavage may release this enzyme to further cleave DNA
- membrane blebbing
- breakdown of the cell into membrane-bound apoptotic bodies (apoptosomes)
- bodies then phagocytosed by other cells
Experimentally a number of different techniques have been developed and are now used to identify these changes.
Regulators can initiate or block apoptosis, the regulators shown block apoptosis.
|Regulator →||Adaptor →||Effector|
|C. elegans||Ced-9 →||Ced-4 →||Ced-3 →||Death|
|Vertebrates||Bcl-2 →||Apaf-1 →||Caspase-9 →||Caspase-3 →||Death|
- ↑ Hiroshi Ueda, Ryousuke Fujita, Akira Yoshida, Hayato Matsunaga, Mutsumi Ueda Identification of prothymosin-alpha1, the necrosis-apoptosis switch molecule in cortical neuronal cultures. J. Cell Biol.: 2007, 176(6);853-62 PMID:17353361 | PMC2064059 | J Cell Biol.
- ↑ J F Kerr, A H Wyllie, A R Currie Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br. J. Cancer: 1972, 26(4);239-57 PMID:4561027
- ↑ Akiko Koto, Masayuki Miura Who lives and who dies: Role of apoptosis in quashing developmental errors. Commun Integr Biol: 2011, 4(4);495-7 PMID:21966582
- ↑ Sandra Leidenfrost, Marc Boelhauve, Myriam Reichenbach, Tuna Güngör, Horst-Dieter Reichenbach, Fred Sinowatz, Eckhard Wolf, Felix A Habermann Cell arrest and cell death in mammalian preimplantation development: lessons from the bovine model. PLoS ONE: 2011, 6(7);e22121 PMID:21811561 | PLoS One.
- ↑ Amitabha Bandyopadhyay, Kunikazu Tsuji, Karen Cox, Brian D Harfe, Vicki Rosen, Clifford J Tabin Genetic analysis of the roles of BMP2, BMP4, and BMP7 in limb patterning and skeletogenesis. PLoS Genet.: 2006, 2(12);e216 PMID:17194222 | PMC1713256
Molecular Biology of the Cell
Alberts, Bruce; Johnson, Alexander; Lewis, Julian; Raff, Martin; Roberts, Keith; Walter, Peter New York and London: Garland Science; c2002
- Molecular Biology of the Cell 4th ed. - IV. Internal Organization of the Cell Chapter 17. The Cell Cycle and Programmed Cell Death
- The Cell Cycle and Programmed Cell Death
- Programmed Cell Death (Apoptosis)
- Figure 17-37. Cell death
- Figure 17-47. Two ways in which survival factors suppress apoptosis
- Figure 17-42. Cell-cycle arrest or apoptosis induced by excessive stimulation of mitogenic pathways
- Figure 17-38. The caspase cascade involved in apoptosis
Molecular Cell Biology
Lodish, Harvey; Berk, Arnold; Zipursky, S. Lawrence; Matsudaira, Paul; Baltimore, David; Darnell, James E. New York: W. H. Freeman & Co.; c1999
- Molecular Cell Biology - Chapter 23. Cell Interactions in Development
- Cell Death and Its Regulation
- Figure 23-50. Current models of the intracellular pathways leading to cell death by apoptosis or to trophic factor–mediated cell survival in mammalian cells
- Movie: Apoptosis
The Cell- A Molecular Approach
Cooper, Geoffrey M. Sunderland (MA): Sinauer Associates, Inc.; c2000
- The Cell - A Molecular Approach - IV. Cell Regulation Chapter 13. Cell Signaling
- Regulation of Programmed Cell Death
External Links Notice - The dynamic nature of the internet may mean that some of these listed links may no longer function. If the link no longer works search the web with the link text or name.
- UNSW Cell Biology - Lecture - Cell Death
- Mechanism Links: Epithelial Invagination | Epithelial Mesenchymal Transition | Epithelial Mesenchymal Interaction | Morphodynamics | Tube Formation | Apoptosis | Molecular
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