Cell lineage

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General stages of cell lineage (cell lineage of liver development in red) Liver cell lineage..jpg
General stages of cell lineage (cell lineage of liver development in red)

Cell lineage denotes the developmental history of a tissue or organ from the fertilized egg. [1] This is based on the tracking of an organism's cellular ancestry due to the cell divisions and relocation as time progresses, this starts with the originator cells and finishing with a mature cell that can no longer divide. [2] [3]

Contents

This type of lineage can be studied by marking a cell (with fluorescent molecules or other traceable markers) and following its progeny after cell division. Some organisms, such as C. elegans, have a predetermined pattern of cell progeny and the adult male will always consist of 1031 cells, this is because cell division in C. elegans is genetically determined and known as eutely. [4] [5] This causes the cell lineage and cell fate to be highly correlated. Other organisms, such as humans, have variable lineages and somatic cell numbers.

C. elegans: model organism

As one of the first pioneers of cell lineage, in the 1960s Dr. Sydney Brenner first began observing cell differentiation and succession in the nematode Caenorhabditis elegans . Dr. Brenner chose this organism due to its transparent body, quick reproduction, ease of access, and small size which made it ideal for following cell lineage under a microscope.

By 1976, Dr. Brenner and his associate, Dr. John Sulston, had identified part of the cell lineage in the developing nervous system of C. elegans. Initial results showed that the nematode was eutelic (each individual experiences the same differentiation pathways), however work by Sulston and Richard Horvitz showed that several cells necessary for reproduction differentiate after hatching. These cells include vulval cells as well as muscle and neurons. This research also led to the initial observations of programmed cell death, or apoptosis.

After mapping various sections of the C. elegans' cell lineage, Dr. Brenner and his associates were able to piece together the first complete and reproducible fate map of cell lineage. They later received the 2002 Nobel prize for their work in genetic regulation of organ development and programmed cell death. [6] Being that C. elegans are hermaphrodites, there consist of both male and female organs, where they store sperm and are able to self fertilize. C. elegans contain 302 neurons and 959 somatic cells, where they begin with 1031, where 72 undergo apoptosis which is programmed cell death. This makes C. elegans a model organism for studying cell lineage, and being able to observe the cell divisions due to their transparent phenotype. [7]

History of cell lineage

One of the first studies of cell lineages took place in the 1870s by Whitman who studied cleavage patterns in leeches and small invertebrates. He found that some groups, such as nematode worms and ascidians form a pattern of cell division which is identical between individuals and invariable. This high correlation between cell lineage and cell fate was thought to be determined by segregating factors within the dividing cells. Other organisms had stereotyped patterns of cell division and produced sublineages which were the progeny of particular precursor cells. These more variable cell fates are thought to be due to the cells' interaction with the environment. Due to new breakthroughs in tracking cells with greater accuracy, this aided the biological community since a variety of colors are now used in showing the original cells and able to track easily. These colors are fluorescent and marked on the proteins by administering injections to trace such cells. [8]

Techniques of fate mapping

Cell lineage can be determined by two methods, either through direct observation or through clonal analysis. During the early 19th century direct observation was used however it was highly limiting as only small transparent samples could be studied. With the invention of the confocal microscope this allowed larger more complicated organisms to be studied. [9]

Perhaps the most popular method of cell fate mapping in the genetic era is through site-specific recombination mediated by the Cre-Lox or FLP-FRT systems. By utilizing the Cre-Lox or FLP-FRT recombination systems, a reporter gene (usually encoding a fluorescent protein) is activated and permanently labels the cell of interest and its offspring cells, thus the name cell lineage tracing. [10] With the system, researchers could investigate the function of their favorite gene in determining cell fate by designing a genetic model where within a cell one recombination event is designed for manipulating the gene of interest and the other recombination event is designed for activating a reporter gene. One minor issue is that the two recombination events may not occur simultaneously thus the results need to be interpreted with caution. [11] Furthermore, some fluorescent reporters have such an extremely low recombination threshold that they may label cell populations at undesired time-points in the absence of induction. [12]

Synthetic biology approaches and the CRISPR/Cas9 system to engineer new genetic systems that enable cells to autonomously record lineage information in their own genome have been developed. These systems are based on engineered, targeted mutation of defined genetic elements. [13] [14] By generating new, random genomic alterations in each cell generation these approaches facilitate reconstruction of lineage trees. These approaches promise to provide more comprehensive analysis of lineage relationships in model organisms. Computational tree reconstruction methods [15] are also being developed for datasets generated by such approaches.

Early developmental asymmetries

In humans after fertilization, the zygote divides into two cells. Somatic mutations that arise directly after the formation of the zygote, as well as later in development, can be used as markers to trace cell lineages throughout the body. [16] Beginning with cleavages of the zygote, lineages were observed to contribute unequally to blood cells. As much as 90% of blood cells were found to be derived from just one of the first two blastomeres. In addition, normal development may result in unequal characteristics of symmetrical organs, such as between the left and right frontal and occipital cerebral cortex. It was proposed that the efficiency of DNA repair contributes to lineage imbalance, as additional time spent by a cell on DNA repair may decrease proliferation rate. [16]

See also

Related Research Articles

<i>Caenorhabditis elegans</i> Free-living species of nematode

Caenorhabditis elegans is a free-living transparent nematode about 1 mm in length that lives in temperate soil environments. It is the type species of its genus. The name is a blend of the Greek caeno- (recent), rhabditis (rod-like) and Latin elegans (elegant). In 1900, Maupas initially named it Rhabditides elegans. Osche placed it in the subgenus Caenorhabditis in 1952, and in 1955, Dougherty raised Caenorhabditis to the status of genus.

Howard Robert Horvitz ForMemRS NAS AAA&S APS NAM is an American biologist whose research on the nematode worm Caenorhabditis elegans was awarded the 2002 Nobel Prize in Physiology or Medicine, together with Sydney Brenner and John E. Sulston, whose "seminal discoveries concerning the genetic regulation of organ development and programmed cell death" were "important for medical research and have shed new light on the pathogenesis of many diseases".

<span class="mw-page-title-main">John Sulston</span> British biologist and academic (1942–2018)

Sir John Edward Sulston was a British biologist and academic who won the Nobel Prize in Physiology or Medicine for his work on the cell lineage and genome of the worm Caenorhabditis elegans in 2002 with his colleagues Sydney Brenner and Robert Horvitz at the MRC Laboratory of Molecular Biology. He was a leader in human genome research and Chair of the Institute for Science, Ethics and Innovation at the University of Manchester. Sulston was in favour of science in the public interest, such as free public access of scientific information and against the patenting of genes and the privatisation of genetic technologies.

Cre-Lox recombination is a site-specific recombinase technology, used to carry out deletions, insertions, translocations and inversions at specific sites in the DNA of cells. It allows the DNA modification to be targeted to a specific cell type or be triggered by a specific external stimulus. It is implemented both in eukaryotic and prokaryotic systems. The Cre-lox recombination system has been particularly useful to help neuroscientists to study the brain in which complex cell types and neural circuits come together to generate cognition and behaviors. NIH Blueprint for Neuroscience Research has created several hundreds of Cre driver mouse lines which are currently used by the worldwide neuroscience community.

<span class="mw-page-title-main">FLP-FRT recombination</span> Site-directed recombination technology

In genetics, Flp-FRT recombination is a site-directed recombination technology, increasingly used to manipulate an organism's DNA under controlled conditions in vivo. It is analogous to Cre-lox recombination but involves the recombination of sequences between short flippase recognition target (FRT) sites by the recombinase flippase (Flp) derived from the 2 μ plasmid of baker's yeast Saccharomyces cerevisiae.

Within the field of developmental biology, one goal is to understand how a particular cell develops into a final cell type, known as fate determination. Within an embryo, several processes play out at the cellular and tissue level to create an organism. These processes include cell proliferation, differentiation, cellular movement and programmed cell death. Each cell in an embryo receives molecular signals from neighboring cells in the form of proteins, RNAs and even surface interactions. Almost all animals undergo a similar sequence of events during very early development, a conserved process known as embryogenesis. During embryogenesis, cells exist in three germ layers, and undergo gastrulation. While embryogenesis has been studied for more than a century, it was only recently that scientists discovered that a basic set of the same proteins and mRNAs are involved in embryogenesis. Evolutionary conservation is one of the reasons that model systems such as the fly, the mouse, and other organisms are used as models to study embryogenesis and developmental biology. Studying model organisms provides information relevant to other animals, including humans. While studying the different model systems, cells fate was discovered to be determined via multiple ways, two of which are by the combination of transcription factors the cells have and by the cell-cell interaction. Cells' fate determination mechanisms were categorized into three different types, autonomously specified cells, conditionally specified cells, or syncytial specified cells. Furthermore, the cells' fate was determined mainly using two types of experiments, cell ablation and transplantation. The results obtained from these experiments, helped in identifying the fate of the examined cells.

Apoptosis is the process of programmed cell death. From its early conceptual beginnings in the 1950s, it has exploded as an area of research within the life sciences community. As well as its implication in many diseases, it is an integral part of biological development.

Balancer chromosomes are a type of genetically engineered chromosome used in laboratory biology for the maintenance of recessive lethal mutations within living organisms without interference from natural selection. Since such mutations are viable only in heterozygotes, they cannot be stably maintained through successive generations and therefore continually lead to production of wild-type organisms, which can be prevented by replacing the homologous wild-type chromosome with a balancer. In this capacity, balancers are crucial for genetics research on model organisms such as Drosophila melanogaster, the common fruit fly, for which stocks cannot be archived. They can also be used in forward genetics screens to specifically identify recessive lethal mutations. For that reason, balancers are also used in other model organisms, most notably the nematode worm Caenorhabditis elegans and the mouse.

<span class="mw-page-title-main">Fate mapping</span>

Fate mapping is a method used in developmental biology to study the embryonic origin of various adult tissues and structures. The "fate" of each cell or group of cells is mapped onto the embryo, showing which parts of the embryo will develop into which tissue. When carried out at single-cell resolution, this process is called cell lineage tracing. It is also used to trace the development of tumors. Fate mapping and cell lineage are similar methods for tracing the history of cells.

John Graham White is an Emeritus Professor of Anatomy and Molecular Biology at the University of Wisconsin–Madison. His research interests are in the biology of the model organism Caenorhabditis elegans and laser microscopy.

<span class="mw-page-title-main">Animal testing on invertebrates</span> Overview article

Most animal testing involves invertebrates, especially Drosophila melanogaster, a fruit fly, and Caenorhabditis elegans, a nematode. These animals offer scientists many advantages over vertebrates, including their short life cycle, simple anatomy and the ease with which large numbers of individuals may be studied. Invertebrates are often cost-effective, as thousands of flies or nematodes can be housed in a single room.

<span class="mw-page-title-main">Brainbow</span> Neuroimaging technique to differentiate neurons

Brainbow is a process by which individual neurons in the brain can be distinguished from neighboring neurons using fluorescent proteins. By randomly expressing different ratios of red, green, and blue derivatives of green fluorescent protein in individual neurons, it is possible to flag each neuron with a distinctive color. This process has been a major contribution to the field of neural connectomics.

The nematode worm Caenorhabditis elegans was first studied in the laboratory by Victor Nigon and Ellsworth Dougherty in the 1940s, but came to prominence after being adopted by Sydney Brenner in 1963 as a model organism for the study of developmental biology using genetics. In 1974, Brenner published the results of his first genetic screen, which isolated hundreds of mutants with morphological and functional phenotypes, such as being uncoordinated. In the 1980s, John Sulston and co-workers identified the lineage of all 959 cells in the adult hermaphrodite, the first genes were cloned, and the physical map began to be constructed. In 1998, the worm became the first multi-cellular organism to have its genome sequenced. Notable research using C. elegans includes the discoveries of caspases, RNA interference, and microRNAs. Eight scientists have won the Nobel Prize for their work on C. elegans.

<span class="mw-page-title-main">Floxing</span> Genetic engineering technique

In genetic engineering, floxing refers to the insertion of a DNA sequence between two LoxP sequences, creating an artificial gene cassette which can then be conditionally deleted, translocated, or inverted in a process called Cre-Lox recombination. Recombination between LoxP sites is catalysed by Cre recombinase. The term "floxing" is a portmanteau constructed from the phrase "flanking/flanked by LoxP".

Judith Kimble is a Henry Vilas Professor of Biochemistry, Molecular Biology, Medical Genetics and Cell and Regenerative Biology at the University of Wisconsin–Madison and Investigator with the Howard Hughes Medical Institute (HHMI). Kimble’s research focuses on the molecular regulation of animal development.

Ced-3 is one of the major protein components of the programmed cell death (PCD) pathway for Caenorhabditis elegans. There are in total 14 genes that are involved in programmed cell death, other important ones including ced-4 and ced-9 genes. The healthy nematode worm will require 131 somatic cell deaths out of the 1090 cells during the developmental stages. The gene initially encodes for a prototypical caspase (procaspase) where the active cysteine residue cleaves aspartate residues, thus becoming a functional caspase. Ced-3 is an executioner caspase that must dimerize with itself and be initiated by ced-4 in order to become active. Once active, it will have a series of reactions that will ultimately lead to the apoptosis of targeted cells.

Worm bagging is a form of vivipary observed in nematodes, namely Caenorhabditis elegans. The process is characterized by eggs hatching within the parent and the larvae proceeding to consume and emerge from the parent.

Eileen Southgate is a British biologist who mapped the complete nervous system of the roundworm Caenorhabditis elegans, together with John White, Nichol Thomson, and Sydney Brenner. The work, done largely by hand-tracing thousands of serial section electron micrographs, was the first complete nervous system map of any animal and it helped establish C. elegans as a model organism. Among other projects carried out as a laboratory assistant at the Medical Research Council Laboratory of Molecular Biology (MRC-LMB), Southgate contributed to work on solving the structure of hemoglobin with Max Perutz and John Kendrew, and investigating the causes of sickle cell disease with Vernon Ingram.

Paul W. Sternberg is an American biologist. He does research for WormBase on C. elegans, a model organism.

<span class="mw-page-title-main">GESTALT</span> Method for lineage tracing using CRISPR-Cas9-edited barcodes

Genome editing of synthetic target arrays for lineage tracing (GESTALT) is a method used to determine the developmental lineages of cells in multicellular systems. GESTALT involves introducing a small DNA barcode that contains regularly spaced CRISPR/Cas9 target sites into the genomes of progenitor cells. Alongside the barcode, Cas9 and sgRNA are introduced into the cells. Mutations in the barcode accumulate during the course of cell divisions and the unique combination of mutations in a cell's barcode can be determined by DNA or RNA sequencing to link it to a developmental lineage.

References

  1. ↑ Collins English Dictionary - Complete & Unabridged 10th Edition. HarperCollins Publishers. Retrieved 2 June 2014.
  2. ↑ Giurumescu, Claudiu A.; Chisholm, Andrew D. (2011). "Cell Identification and Cell Lineage Analysis". Methods in Cell Biology. 106: 325–341. doi:10.1016/B978-0-12-544172-8.00012-8. ISBN   9780125441728. ISSN   0091-679X. PMC   4410678 . PMID   22118283.
  3. ↑ Cell line generation
  4. ↑ Sulston, JE; Horvitz, HR (1977). "Post-embryonic cell lineages of the nematode, Caenorhabditis elegans". Developmental Biology . 56 (1): 110–56. doi:10.1016/0012-1606(77)90158-0. PMID   838129.
  5. ↑ Kimble, J; Hirsh, D (1979). "The postembryonic cell lineages of the hermaphrodite and male gonads in Caenorhabditis elegans". Developmental Biology . 70 (2): 396–417. doi:10.1016/0012-1606(79)90035-6. PMID   478167.
  6. ↑ "The Nobel Prize in Physiology or Medicine for 2002 - Press Release". www.nobelprize.org. Retrieved 2015-11-23.
  7. ↑ Corsi, Ann K. (2006-12-01). "A Biochemist's Guide to C. elegans". Analytical Biochemistry. 359 (1): 1–17. doi:10.1016/j.ab.2006.07.033. ISSN   0003-2697. PMC   1855192 . PMID   16942745.
  8. ↑ Woodworth, Mollie B.; Girskis, Kelly M.; Walsh, Christopher A. (April 2017). "Building a lineage from single cells: genetic techniques for cell lineage tracking". Nature Reviews. Genetics. 18 (4): 230–244. doi:10.1038/nrg.2016.159. ISSN   1471-0056. PMC   5459401 . PMID   28111472.
  9. ↑ Chisholm, A D (2001). "Cell Lineage" (PDF). Encyclopedia of Genetics. pp. 302–310. doi:10.1006/rwgn.2001.0172. ISBN   9780122270802.[ permanent dead link ]
  10. ↑ Kretzschemar, K; Watt, F.M. (Jan 12, 2012). "Lineage tracing". Cell. 148 (1–2): 33–45. doi: 10.1016/j.cell.2012.01.002 . PMID   22265400.
  11. ↑ Liu, J; Willet, SG; Bankaitis, ED (2013). "Non-parallel recombination limits Cre-LoxP-based reporters as precise indicators of conditional genetic manipulation". Genesis. 51 (6): 436–42. doi:10.1002/dvg.22384. PMC   3696028 . PMID   23441020.
  12. ↑ Álvarez-Aznar, A.; Martínez-Corral, I.; Daubel, N.; Betsholtz, C.; Mäkinen, T.; Gaengel, K. (2020). "Tamoxifen-independent recombination of reporter genes limits lineage tracing and mosaic analysis using CreERT2 lines". Transgenic Research. 29 (1): 53–68. doi:10.1007/s11248-019-00177-8. ISSN   0962-8819. PMC   7000517 . PMID   31641921.
  13. ↑ McKenna, Aaron; Findlay, Gregory M.; Gagnon, James A.; Horwitz, Marshall S.; Schier, Alexander F.; Shendure, Jay (2016-07-29). "Whole-organism lineage tracing by combinatorial and cumulative genome editing". Science. 353 (6298): aaf7907. doi:10.1126/science.aaf7907. ISSN   0036-8075. PMC   4967023 . PMID   27229144.
  14. ↑ Frieda, Kirsten L.; Linton, James M.; Hormoz, Sahand; Choi, Joonhyuk; Chow, Ke-Huan K.; Singer, Zakary S.; Budde, Mark W.; Elowitz, Michael B.; Cai, Long (2017). "Synthetic recording and in situ readout of lineage information in single cells". Nature. 541 (7635): 107–111. Bibcode:2017Natur.541..107F. doi:10.1038/nature20777. PMC   6487260 . PMID   27869821.
  15. ↑ Zafar, Hamim; Lin, Chieh; Bar-Joseph, Ziv (2020). "Single-cell lineage tracing by integrating CRISPR-Cas9 mutations with transcriptomic data". Nature Communications. 11 (3055): 3055. Bibcode:2020NatCo..11.3055Z. doi: 10.1038/s41467-020-16821-5 . PMC   7298005 . PMID   32546686.
  16. 1 2 Fasching L, Jang Y, Tomasi S, Schreiner J, Tomasini L, Brady MV, Bae T, Sarangi V, Vasmatzis N, Wang Y, Szekely A, Fernandez TV, Leckman JF, Abyzov A, Vaccarino FM (19 March 2021). "Early developmental asymmetries in cell lineage trees in living individuals". Science. 371 (6535): 1245–1248. Bibcode:2021Sci...371.1245F. doi:10.1126/science.abe0981. PMC   8324008 . PMID   33737484.
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