Developmental Mechanism - Apoptosis

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Introduction

Neuron apoptosis or necrosis (EM).[1]

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.[2]


Greek, ptosis= "falling", as in when leaves fall from a tree in autumn.


Mechanism Links: mitosis | cell migration | epithelial invagination | epithelial mesenchymal transition | mesenchymal epithelial transition | epithelial mesenchymal interaction | morphodynamics | tube formation | apoptosis | autophagy | axes formation | time | molecular

Cell Biology Lecture - Cell Death

Some Recent Findings

  • Caspases and matrix metalloproteases facilitate collective behavior of non-neural ectoderm after hindbrain neuropore closure[3] "Mammalian brain is formed through neural tube closure (NTC), wherein both ridges of opposing neural folds are fused in the midline and remodeled in the roof plate of the neural tube and overlying non-neural ectodermal layer. Apoptosis is widely observed from the beginning of NTC at the neural ridges and is crucial for the proper progression of NTC, but its role after the closure remains less clear. RESULTS: Here, we conducted live-imaging analysis of the mid-hindbrain neuropore (MHNP) closure and revealed unexpected collective behavior of cells surrounding the MHNP. The cells first gathered to the closing point and subsequently relocated as if they were released from the point. Inhibition of caspases or matrix metalloproteases with chemical inhibitors impaired the cell relocation. CONCLUSIONS: These lines of evidence suggest that apoptosis-mediated degradation of extracellular matrix might facilitate the final process of neuropore closure."
  • Who lives and who dies: Role of apoptosis in quashing developmental errors[4] "Apoptosis is essential for normal development. Large numbers of cells are eliminated by apoptosis in early neural development and during the formation of neural connections. However, our understanding of this life-or-death decision is incomplete, because it is difficult to identify dying cells by conventional strategies. Live imaging is powerful for studying apoptosis, because it can trace a death-fated cell throughout its lifetime. The Drosophila sensory organ development is a convenient system for studying neural-cell selection via lateral inhibition. We recently showed that about 20% of the differentiating neuronal cells die during sensory organ development, which results in the characteristic spatial patterning of the sensory organs. The eliminated differentiating neurons expressed neurogenic genes and high levels of activated Notch. Thus, live imaging allowed us to document the role of apoptosis in neural progenitor selection, and revealed that Notch activation is the mechanism determining which cells die during sensory organ development."
More recent papers  
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Search term: Development Apoptosis

Older papers  
These papers originally appeared in the Some Recent Findings table, but as that list grew in length have now been shuffled down to this collapsible table.

See also the Discussion Page for other references listed by year and References on this current page.

Developmental Examples

Blastocyst Development

Removing cells from the developing inner cell mass.


Links: Blastocyst Development
Bovine blastocyst 01.jpg

Cell death in bovine blastocyst[5]

Cloacal Membrane Development

The initial cloaca is the common early endoderm lined space of the hindgut that will later become partitioned by a septum into a dorsal gastrointestinal component (rectum) and ventral renal/genital component (urogenital sinus). Located at the inferior end of the cloaca is the cloacal membrane, that also forms part of the embryo surface. The cloacal membrane is formed during gastrulation by ectoderm and endoderm without a middle (intervening) layer of mesoderm, and later degenerates by apoptosis[6][7] after cloacal septation in mammals.


Links: cloacal membrane

Digit Development

Removing cells between digits (fingers and toes) of the upper and lower limbs.



Links: Limb Development


Mouse interdigit apoptosis 01.jpg

Interdigital apoptosis in the mous hindlimb.[8]

Bone development

During ossification removing chondrocytes.


Links: bone

Neural development

Removing excess or inappropriately connected neurons.


Links: neural

Ovary Development

Removing excess primordial follicles from the ovary cortex.


Links: ovary

Mammary Development

Mammary involution[9]

Mammary involution.jpg

  1. Milk stasis induces the expression of leukaemia inhibitory factor (LIF) and transforming growth factor (TGF)β3 within 12 hours of forced weaning.
  2. These, in turn, phosphorylate and activate the transcription factor Stat3.
  3. This results in the induction of apoptosis and shedding of dying cells into the alveolar lumen.
  4. Neighbouring cells migrate to close the gap and maintain the integrity of the alveolar structure.
  1. Concurrently with these events, members of the death receptor ligand family and their receptors are transcriptionally upregulated and this induces apoptosis through activation of caspase 8.
  2. Downstream targets of these pathways are then induced and ensure the transition to the second phase.
  3. Following this reversible first phase, matrix metalloproteases (MMP) begin to break down the ECM surrounding each alveolus, resulting in detachment induced apoptosis and collapse of the alveoli.
  4. Remodelling is then completed by re-differentiation of the adipoctyes which requires the action of plasmin and MMP3.

Full involution returns the gland to a pre-pregnant state. ECM, extracellular matrix.


Links: mammary gland

Renal Development

In the rat model of renal development, apoptotic death has been found in both the nephrogenic region and medullary papilla.[10] (See recent review[11])


Links: {{Renal))

Genital Development

Reciprocal Spatiotemporally Controlled apoptosis Regulates Wolffian Duct Cloaca Fusion[12]

"The epithelial Wolffian duct (WD) inserts into the cloaca (primitive bladder) before metanephric kidney development, thereby establishing the initial plumbing for eventual joining of the ureters and bladder. Defects in this process cause common anomalies in the spectrum of congenital anomalies of the kidney and urinary tract (CAKUT). However, developmental, cellular, and molecular mechanisms of WD-cloaca fusion are poorly understood. Through systematic analysis of early WD tip development in mice, we discovered that a novel process of spatiotemporally regulated apoptosis in WD and cloaca was necessary for WD-cloaca fusion. Aberrant RET tyrosine kinase signaling through tyrosine (Y) 1062, to which PI3K- or ERK-activating proteins dock, or Y1015, to which PLCγ docks, has been shown to cause CAKUT-like defects. Cloacal apoptosis did not occur in RetY1062F mutants, in which WDs did not reach the cloaca, or in RetY1015F mutants, in which WD tips reached the cloaca but did not fuse. Moreover, inhibition of ERK or apoptosis prevented WD-cloaca fusion in cultures, and WD-specific genetic deletion of YAP attenuated cloacal apoptosis and WD-cloacal fusion in vivo Thus, cloacal apoptosis requires direct contact and signals from the WD tip and is necessary for WD-cloacal fusion. These findings may explain the mechanisms of many CAKUT."
Links: genital | testis

Worm Development

Worm - embryonic cell lineage 02.jpg

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.


Links: Worm Development | Worm Atlas - Cell Lineages


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

Adult Examples

Bacterial Infection

This movie from an in vitro experimental bacterial infection of Hela cells with Neisseria gonorrhoeae shows the cells dying by apoptosis.


Apoptosis is a form of programmed cell death that occurs normally in many developmental and adult tissues, but can also occur in response to pathogenic infections.


The same movie is shown below without the added labels.



Apoptosis Links: Hela Apoptosis Movie | MP4 labeled | MP4 unlabeled | Gonorrhea | Bacterial Infection | Apoptosis | Movies



Cell apoptosis icon.jpg
 ‎‎Hela Apoptosis
Page | Play

Apoptotic Cell Morphology

File:Apoptosis DNA ladder.jpg
Apoptosis DNA ladder

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
  • 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.

Links:


Apoptosis Regulators

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


p63

p63 (tumor protein p63) gene (3q28) encodes a transcription factor with multiple isotypes that transactivate p53 reporter genes and induce apoptosis. For example, during palate development p63 can exert spatio-temporal control of palatal epithelial cell fate to prevent cleft palate [13]


Links: OMIM p63


Necrosis

Neural apoptosis and necrosis

Necrosis (Greek, nekros = corpse) is not a form of developmental cell death, but a pathological cell death from extrinsic injury (tissue damage) and is irreversible. Necrosis is induced by tumor necrosis factor, double-stranded RNA, viral infection or bacterial infection toxins.

In the early stages, cell and organelles (mitochondria) swell (oncosis) (Greek, onkos = 'swelling') previously described as a separate form of cell death. This is due to disruption of plasma membrane leading to cell contents leak out leading to inflammation and necrosis.

In the late stages, there is a loss of cell membrane integrity, finally cell disintegration. This cell lysis can also trigger an inflammatory response, leading to further inflammation and damage, and triggering a cycle of death

  • Bacteria - S. aureus - pore-forming secreted toxins can induce necrosis
  • Prothymosin-alpha 1 - (ProT) inhibits necrosis, switches cells from necrosis to apoptosis


References

  1. Ueda H, Fujita R, Yoshida A, Matsunaga H & Ueda M. (2007). Identification of prothymosin-alpha1, the necrosis-apoptosis switch molecule in cortical neuronal cultures. J. Cell Biol. , 176, 853-62. PMID: 17353361 DOI.
  2. . (). . , , . PMID: 45610271
  3. Shinotsuka N, Yamaguchi Y, Nakazato K, Matsumoto Y, Mochizuki A & Miura M. (2018). Caspases and matrix metalloproteases facilitate collective behavior of non-neural ectoderm after hindbrain neuropore closure. BMC Dev. Biol. , 18, 17. PMID: 30064364 DOI.
  4. Koto A & Miura M. (2011). Who lives and who dies: Role of apoptosis in quashing developmental errors. Commun Integr Biol , 4, 495-7. PMID: 21966582 DOI.
  5. Leidenfrost S, Boelhauve M, Reichenbach M, Güngör T, Reichenbach HD, Sinowatz F, Wolf E & Habermann FA. (2011). Cell arrest and cell death in mammalian preimplantation development: lessons from the bovine model. PLoS ONE , 6, e22121. PMID: 21811561 DOI.
  6. Miller SA, Clark C, Cooney R, Crary E & Payzant W. (1998). Apoptosis fenestrates chick cloacal membrane and occluded rectal cord and may have a minor role in removal of pharyngeal membranes. Ann. N. Y. Acad. Sci. , 857, 268-71. PMID: 9917854
  7. Sasaki C, Yamaguchi K & Akita K. (2004). Spatiotemporal distribution of apoptosis during normal cloacal development in mice. Anat Rec A Discov Mol Cell Evol Biol , 279, 761-7. PMID: 15278947 DOI.
  8. Bandyopadhyay A, Tsuji K, Cox K, Harfe BD, Rosen V & Tabin CJ. (2006). Genetic analysis of the roles of BMP2, BMP4, and BMP7 in limb patterning and skeletogenesis. PLoS Genet. , 2, e216. PMID: 17194222 DOI.
  9. Watson CJ. (2006). Involution: apoptosis and tissue remodelling that convert the mammary gland from milk factory to a quiescent organ. Breast Cancer Res. , 8, 203. PMID: 16677411 DOI.
  10. Coles HS, Burne JF & Raff MC. (1993). Large-scale normal cell death in the developing rat kidney and its reduction by epidermal growth factor. Development , 118, 777-84. PMID: 8076517
  11. . (). . , , . PMID: 825478553
  12. Hoshi M, Reginensi A, Joens MS, Fitzpatrick JAJ, McNeill H & Jain S. (2018). Reciprocal Spatiotemporally Controlled Apoptosis Regulates Wolffian Duct Cloaca Fusion. J. Am. Soc. Nephrol. , 29, 775-783. PMID: 29326158 DOI.
  13. Richardson R, Mitchell K, Hammond NL, Mollo MR, Kouwenhoven EN, Wyatt ND, Donaldson IJ, Zeef L, Burgis T, Blance R, van Heeringen SJ, Stunnenberg HG, Zhou H, Missero C, Romano RA, Sinha S, Dixon MJ & Dixon J. (2017). p63 exerts spatio-temporal control of palatal epithelial cell fate to prevent cleft palate. PLoS Genet. , 13, e1006828. PMID: 28604778 DOI.


Textbooks

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 Cell Biology

Lodish, Harvey; Berk, Arnold; Zipursky, S. Lawrence; Matsudaira, Paul; Baltimore, David; Darnell, James E. New York: W. H. Freeman & Co.; c1999

The Cell- A Molecular Approach

Cooper, Geoffrey M. Sunderland (MA): Sinauer Associates, Inc.; c2000

Reviews

Articles

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Cite this page: Hill, M.A. (2019, July 16) Embryology Developmental Mechanism - Apoptosis. Retrieved from https://embryology.med.unsw.edu.au/embryology/index.php/Developmental_Mechanism_-_Apoptosis

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