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Structure of the RNA-tagging machinery shows that only one pair
of proteins (blue) can add tags to the RNA (red) at a time.
Image Credit: CELL, 14 November 2013
Senescence as a function of (LEFT) Embryo Development, in (RIGHT) Cancer
Image Credit: CELL, 14 November 2013
Senescence also plays a role in embryo development
Researchers propose that senescence appeared in embryos as a switch to turn off cells that are no longer useful — not simply at the end of an organism's life. One of the main mechanisms the body uses to protect itself against cancer is to switch off defective cells by making them senescent which stops a cell from dividing.
This switching-off mechanism also takes place in embryos, and not as a response to cell damage but as part the normal process of development — suggests a team of researchers from the Spanish National Cancer Research Centre (CNIO) in Madrid and another one from the Centre for Genomic Regulation (CRG) in Barcelona. The research is published in two articles in the journal Cell (1) "Programmed Cell Senescence during Mammalian Embryonic Development" and (2) "Senescence Is a Developmental Mechanism that Contributes to Embryonic Growth and Patterning."
As the embryo grows, and its tissues change shape and function, senescence switches off cells that are no longer necessary. These switched-off cells are later recognized and eliminated by a special type of cells of the immune system known as macrophages. Senescence during embryonic development has important implications for understanding how the body grows and is shaped.
"We have discovered that cell senescence is a mechanism for tissue remodelling during embryo development. Embryo development is full of recycling: tissues with one function at one point in the process are used for something different further down the line. In this process of redesign, when cells are no longer needed, one way of getting rid of them is to make them senescent."
Manuel Serrano, head of CNIO's Tumour Suppression Group and leader of the study, whose first author is Daniel Muñoz-Espín.
The CRG study was led by Bill Keyes, and the first author is Mekayla Storer.
Senescence is one of the most studied cellular processes because of its relationship to cancer and ageing. It is often presented as a double-edged sword: both as protection against cancer and for its important role in the ageing of the body. The authors of the present study, however, warn against the simplistic idea that ageing is a consequence of senescence.
"In my opinion, senescence is a fundamentally beneficial process, whose goal in adult organisms is to eliminate damaged cells," says Serrano, "what happens is that when we get old there are more damaged cells and consequently there is more senescence." In other words, blaming senescence for ageing is like blaming firefighters for fires just because they are always next to a fire.
The two new articles published in Cell offer a new perspective on the concept of senescence. The researchers have not only detected senescence in the embryo, they have also identified the genes that activate and regulate the process — and have studied what happens when they prevent senescence experimentally. To distinguish senescence as a defence mechanism as different from senescence in normal embryonic development, they identify the latter process as "programmed senescence."
Furthermore, they conclude senescence appeared during evolution as a developmental process and, later was adapted as a defence mechanism by adult organisms.
"Conceptually, we add cellular senescence to the collection of processes that contribute to embryonic development. This opens up the possibility that cellular senescence originated during evolution as an embryonic tissue-remodelling process, a function that later evolved to become a damage and stress response."
The CNIO authors worked with mouse and human embryos, while the CRG team worked with chicken and mouse embryos, both teams observed senescence in all three species. They highlight that their observations "support the idea that senescence is widespread during the embryonic development of vertebrates."
It turns out that genes involved in programmed senescence are the same for the mesonephros as for the endolymphatic sac: "It is telling that two independent development processes share the same critical effector and the same regulatory routes," say the authors in their article in Cell.
The mesonephros is an early tissue that functions as a kidney during development and later almost completely disappears — leaving only a tube forming the vas deferens and the epididymis in the testicles and participates in the formation of the vagina.
The endolymphatic sac is also an important structure of the inner ear.
Senescence leaves a characteristic chemical signature in cells. CNIO researchers looked for it specifically in these two embryo structures.
The gene that activates the process in the two structures analysed, which exist in both mouse and human embryos, is called p21.
When p21 cannot turn on, there is no senescence. Despite partial compensation for this defect by other mechanisms, it is possible to detect, for example, problems in the formation of the vagina.
What happens in embryonic tissues once programmed senescence has switched off the unwanted cells? Macrophages, cells of the defence-system, eliminate the useless cells and remodel the tissue.
The authors consider this to be a first study that opens up new horizons. Soon, they say, programmed senescence will be detected in many other developmental processes.
Cell (1) "Programmed Cell Senescence during Mammalian Embryonic Development"
Senescence occurs in a programmed manner during normal mammalian development
The studied processes of senescence depend on p21 and the TGF-β and PI3K pathways
Senescent cells are cleared by macrophages, which results in tissue remodeling
Loss of senescence affects morphogenesis despite partial compensation by apoptosis
Cellular senescence disables proliferation in damaged cells, and it is relevant for cancer and aging. Here, we show that senescence occurs during mammalian embryonic development at multiple locations, including the mesonephros and the endolymphatic sac of the inner ear, which we have analyzed in detail. Mechanistically, senescence in both structures is strictly dependent on p21, but independent of DNA damage, p53, or other cell-cycle inhibitors, and it is regulated by the TGF-β/SMAD and PI3K/FOXO pathways. Developmentally programmed senescence is followed by macrophage infiltration, clearance of senescent cells, and tissue remodeling. Loss of senescence due to the absence of p21 is partially compensated by apoptosis but still results in detectable developmental abnormalities. Importantly, the mesonephros and endolymphatic sac of human embryos also show evidence of senescence. We conclude that the role of developmentally programmed senescence is to promote tissue remodeling and propose that this is the evolutionary origin of damage-induced senescence.
Daniel Muñoz-Espín, Marta Cañamero, Antonio Maraver, Gonzalo Gómez-López, Julio Contreras, Silvia Murillo-Cuesta, Alfonso Rodríguez-Baeza, Isabel Varela-Nieto, Jesús Ruberte, Manuel Collado, Manuel Serrano
Cell (2) "Senescence Is a Developmental Mechanism that Contributes to Embryonic Growth and Patterning"
Cellular senescence is a normal, programmed, and instructive developmental process
Developmental senescence and oncogene-induced senescence share common signatures
p21 is a critical mediator of developmental senescence
Senescent cells are removed by apoptosis and macrophage-mediated clearance
Senescence is a form of cell-cycle arrest linked to tumor suppression and aging. However, it remains controversial and has not been documented in nonpathologic states. Here we describe senescence as a normal developmental mechanism found throughout the embryo, including the apical ectodermal ridge (AER) and the neural roof plate, two signaling centers in embryonic patterning. Embryonic senescent cells are nonproliferative and share features with oncogene-induced senescence (OIS), including expression of p21, p15, and mediators of the senescence-associated secretory phenotype (SASP). Interestingly, mice deficient in p21 have defects in embryonic senescence, AER maintenance, and patterning. Surprisingly, the underlying mesenchyme was identified as a source for senescence instruction in the AER, whereas the ultimate fate of these senescent cells is apoptosis and macrophage-mediated clearance. We propose that senescence is a normal programmed mechanism that plays instructive roles in development, and that OIS is an evolutionarily adapted reactivation of a developmental process.
Mekayla Storer, Alba Mas, Alexandre Robert-Moreno, Matteo Pecoraro, M. Carmen Ortells, Valeria Di Giacomo, Reut Yosef, Noam Pilpel, Valery Krizhanovsky, James Sharpe, William M. Keyes
Original press release: http://www.cnio.es/es/news/docs/Manuel-Serrano-Cell-14nov13-en.pdf