Karyogamy

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Karyogamy in the context of cell fusion. 1-haploid cells, 2-cell fusion, 3-single cell with two pronuclei, 4-fusing pronuclei (karyogamy), 5-diploid cell Karyogamy.jpg
Karyogamy in the context of cell fusion. 1-haploid cells, 2-cell fusion, 3-single cell with two pronuclei, 4-fusing pronuclei (karyogamy), 5-diploid cell

Karyogamy is the final step in the process of fusing together two haploid eukaryotic cells, and refers specifically to the fusion of the two nuclei. Before karyogamy, each haploid cell has one complete copy of the organism's genome. In order for karyogamy to occur, the cell membrane and cytoplasm of each cell must fuse with the other in a process known as plasmogamy. Once within the joined cell membrane, the nuclei are referred to as pronuclei. Once the cell membranes, cytoplasm, and pronuclei fuse, the resulting single cell is diploid, containing two copies of the genome. This diploid cell, called a zygote or zygospore can then enter meiosis (a process of chromosome duplication, recombination, and division, to produce four new haploid cells), or continue to divide by mitosis. Mammalian fertilization uses a comparable process to combine haploid sperm and egg cells (gametes) to create a diploid fertilized egg.

Contents

The term karyogamy comes from the Greek karyo- (from κάρυον karyon) meaning "nut" and γάμος gamos, meaning "marriage". [1]

Importance in haploid organisms

Step labeled number 4 indicates karyogamy's place in the context of the life cycle of the fungus Taphrina. Taphrina life cycle.svg
Step labeled number 4 indicates karyogamy's place in the context of the life cycle of the fungus Taphrina.

Haploid organisms such as fungi, yeast, and algae can have complex cell cycles, in which the choice between sexual or asexual reproduction is fluid, and often influenced by the environment. Some organisms, in addition to their usual haploid state, can also exist as diploid for a short time, allowing genetic recombination to occur. Karyogamy can occur within either mode of reproduction: during the sexual cycle or in somatic (non-reproductive) cells. [2]

Thus, karyogamy is the key step in bringing together two sets of different genetic material which can recombine during meiosis. In haploid organisms that lack sexual cycles, karyogamy can also be an important source of genetic variation during the process of forming somatic diploid cells. Formation of somatic diploids circumvents the process of gamete formation during the sexual reproduction cycle and instead creates variation within the somatic cells of an already developed organism, such as a fungus. [2]

Role in sexual reproduction

(a) In fission yeast, the mating process is triggered by nitrogen starvation when compatible partners are present. (b) Budding yeast cells of opposite mating type can instead mate spontaneously on rich medium to form stable diploids that undergo sporulation upon starvation. In both organisms after pheromone exchange, cells grow in a polarized manner in the direction of their partner and undergo fusion, karyogamy and sporulation. Sequential steps during mating in Schizosaccharomyces pombe and Saccharomyces cerevisiae.jpg
(a) In fission yeast, the mating process is triggered by nitrogen starvation when compatible partners are present. (b) Budding yeast cells of opposite mating type can instead mate spontaneously on rich medium to form stable diploids that undergo sporulation upon starvation. In both organisms after pheromone exchange, cells grow in a polarized manner in the direction of their partner and undergo fusion, karyogamy and sporulation.

The role of karyogamy in sexual reproduction can be demonstrated most simply by single-celled haploid organisms such as the algae of genus Chlamydomonas or the yeast Saccharomyces cerevisiae . Such organisms exist normally in a haploid state, containing only one set of chromosomes per cell. However, the mechanism remains largely the same among all haploid eukaryotes. [3]

When subjected to environmental stress, such as nitrogen starvation in the case of Chlamydomonas, cells are induced to form gametes. [4] Gamete formation in single-celled haploid organisms such as yeast is called sporulation, resulting in many cellular changes that increase resistance to stress. Gamete formation in multicellular fungi occurs in the gametangia, an organ specialized for such a process, usually by meiosis. [5] When opposite mating types meet, they are induced to leave the vegetative cycle and enter the mating cycle. In yeast, there are two mating types, a and α. [6] In fungi, there can be two, four, or even up to 10,000 mating types, depending on the species. [7] [8] Mate recognition in the simplest eukaryotes is achieved through pheromone signaling, which induces shmoo formation (a projection of the cell) and begins the process of microtubule organization and migration. Pheromones used in mating type recognition are often peptides, but sometimes trisporic acid or other molecules, recognized by cellular receptors on the opposite cell. Notably, pheromone signaling is absent in higher fungi such as mushrooms. [3]

The cell membranes and cytoplasm of these haploid cells then fuse together in a process known as plasmogamy. This results in a single cell with two nuclei, known as pronuclei. The pronuclei then fuse together in a well regulated process known as karyogamy. This creates a diploid cell known as a zygote, or a zygospore, [4] which can then enter meiosis, a process of chromosome duplication, recombination, and cell division, to create four new haploid gamete cells. One possible advantage of sexual reproduction is that it results in more genetic variability, providing the opportunity for adaptation through natural selection. Another advantage is efficient recombinational repair of DNA damages during meiosis. Thus, karyogamy is the key step in bringing together a variety of genetic material in order to ensure recombination in meiosis. [3]

The Amoebozoa is a large group of mostly single-celled species that have recently been determined to have the machinery for karyogamy and meiosis. [9] Since the Amoeboza branched off early from the eukaryotic family tree, this finding suggests that karyogamy and meiosis were present early in eukaryotic evolution.

Cellular mechanisms

Pronuclear migration

Nucleus is gray; Spindle pole body (SPB) is black circle; Microtubules (MTs) are black bars; actin filaments are gray cables; actin patches are small gray circles. (A) Nuclear orientation to the shmoo tip. (B) MT attachment to the shmoo tip. (C) Before cell-cell fusion, MTs are maintained at the shmoo tip. (D) Sliding cross-bridge model for nuclear congression. Oppositely oriented MTs overlap and are cross-linked along their lengths, whereas depolymerization is induced at the spindle poles. (E) Plus end model for nuclear congression. MT plus ends cross-link and induce depolymerization to draw opposing nuclei together. Schematic of nuclear orientation, cytoplasmic MT attachment to the shmoo tip, and nuclear congression..jpg
Nucleus is gray; Spindle pole body (SPB) is black circle; Microtubules (MTs) are black bars; actin filaments are gray cables; actin patches are small gray circles. (A) Nuclear orientation to the shmoo tip. (B) MT attachment to the shmoo tip. (C) Before cell–cell fusion, MTs are maintained at the shmoo tip. (D) Sliding cross-bridge model for nuclear congression. Oppositely oriented MTs overlap and are cross-linked along their lengths, whereas depolymerization is induced at the spindle poles. (E) Plus end model for nuclear congression. MT plus ends cross-link and induce depolymerization to draw opposing nuclei together.

The ultimate goal of karyogamy is fusion of the two haploid nuclei. The first step in this process is the movement of the two pronuclei toward each other, which occurs directly after plasmogamy. Each pronucleus has a spindle pole body that is embedded in the nuclear envelope and serves as an attachment point for microtubules. Microtubules, an important fiber-like component of the cytoskeleton, emerge at the spindle pole body. The attachment point to the spindle pole body marks the minus end, and the plus end extends into the cytoplasm. The plus end has normal roles in mitotic division, but during nuclear congression, the plus ends are redirected. The microtubule plus ends attach to the opposite pronucleus, resulting in the pulling of the two pronuclei toward each other. [10]

Microtubule movement is mediated by a family of motor proteins known as kinesins, such as Kar3 in yeast. Accessory proteins, such as Spc72 in yeast, act as a glue, connecting the motor protein, spindle pole body and microtubule in a structure known as the half-bridge. Other proteins, such as Kar9 and Bim1 in yeast, attach to the plus end of the microtubules. They are activated by pheromone signals to attach to the shmoo tip. A shmoo is a projection of the cellular membrane which is the site of initial cell fusion in plasmogamy. After plasmogamy, the microtubule plus ends continue to grow towards the opposite pronucleus. It is thought that the growing plus end of the microtubule attaches directly to the motor protein of the opposite pronucleus, triggering a reorganization of the proteins at the half-bridge. The force necessary for migration occurs directly in response to this interaction. [11]

Two models of nuclear congression have been proposed: the sliding cross-bridge, and the plus end model. In the sliding cross-bridge model, the microtubules run antiparallel to each other for the entire distance between the two pronuclei, forming cross-links to each other, and each attaching to the opposite nucleus at the plus end. This is the favored model. The alternative model proposes that the plus ends contact each other midway between the two pronuclei and only overlap slightly. In either model, it is believed that microtubule shortening occurs at the plus end and requires Kar3p (in yeast), a member of a family of kinesin-like proteins. [10]

Microtubule organization in the cytoskeleton has been shown to be essential for proper nuclear congression during karyogamy. Defective microtubule organization causes total failure of karyogamy, but does not totally interrupt meiosis and spore production in yeast. The failure occurs because the process of nuclear congression cannot occur without functional microtubules. Thus, the pronuclei do not approach close enough to each other to fuse together, and their genetic material remains separated. [12]

Pronuclear fusion (karyogamy)

Merging of the nuclear envelopes of the pi occurs in three steps: fusion of the outer membrane, fusion of the inner membrane, and fusion of the spindle pole bodies. In yeast, several members of the Kar family of proteins, as well as a protamine, are required for the fusion of nuclear membranes. The protamine Prm3 is located on the outer surface of each nuclear membrane, and is required for the fusion of the outer membrane. The exact mechanism is not known. Kar5, a kinesin-like protein, is necessary to expand the distance between the outer and inner membranes in a phenomenon known as bridge expansion. Kar8 and Kar2 are thought to be necessary to the fusing of the inner membranes. [13] As described above, the reorganization of accessory and motor proteins during pronuclear migration also serves to orient the spindle pole bodies in the correct direction for efficient nuclear congression. Nuclear congression can still take place without this pre-orientation of spindle pole bodies, but it is slower. Ultimately the two pronuclei combine the contents of their nucleoplasms and form a single envelope around the result. [11]

Role in somatic diploids

Although fungi are normally haploid, diploid cells can arise by two mechanisms. The first is a failure of the mitotic spindle during regular cell division, and does not involve karyogamy. The resulting cell can only be genetically homozygous since it is produced from one haploid cell. The second mechanism, involving karyogamy of somatic cells, can produce heterozygous diploids if the two nuclei differ in genetic information. The formation of somatic diploids is generally rare, and is thought to occur because of a mutation in the karyogamy repressor gene (KR). [2]

There are, however, a few fungi that exist mostly in the diploid state. One example is Candida albicans, a fungus that lives in the gastrointestinal tracts of many warm blooded animals, including humans. Although usually innocuous, C. albicans can turn pathogenic and is a particular problem in immunosuppressed patients. Unlike with most other fungi, diploid cells of different mating types fuse to create tetraploid cells which subsequently return to the diploid state by losing chromosomes. [14]

Similarities to and differences from mammalian fertilization

Mammals, including humans, also combine genetic material from two sources - father and mother - in fertilization. This process is similar to karyogamy. As with karyogamy, microtubules play an important part in fertilization and are necessary for the joining of the sperm and egg (oocyte) DNA. [15] Drugs such as griseofulvin that interfere with microtubules prevent the fusion of the sperm and egg pronuclei. The gene KAR2 which plays a large role in karyogamy has a mammalian analog called Bib/GRP78. [16] In both cases, genetic material is combined to create a diploid cell that has greater genetic diversity than either original source. [17] Instead of fusing in the same way as lower eukaryotes do in karyogamy, the sperm nucleus vesiculates and its DNA decondenses. The sperm centriole acts as a microtubule organizing center and forms an aster which extends throughout the egg until contacting the egg's nucleus. The two pronuclei migrate toward each other and then fuse to form a diploid cell. [18]

See also

Related Research Articles

Gamete Cell that fuses during fertilisation, such as a sperm or egg cell

A gamete is a haploid cell that fuses with another haploid cell during fertilization in organisms that reproduce sexually. Gametes are an organism's reproductive cells, also referred to as sex cells. In species that produce two morphologically distinct types of gametes, and in which each individual produces only one type, a female is any individual that produces the larger type of gamete—called an ovum— and a male produces the smaller type—called a sperm. Sperm cells or spermatozoa are small and motile due to the flagellum, a tail-shaped structure that allows the cell to propel and move. In contrast, each egg cell or ovum is relatively large and non-motile. In short a gamete is an egg cell or a sperm. In animals, ova mature in the ovaries of females and sperm develop in the testes of males. During fertilization, a spermatozoon and ovum unite to form a new diploid organism. Gametes carry half the genetic information of an individual, one ploidy of each type, and are created through meiosis, in which a germ cell undergoes two fissions, resulting in the production of four gametes. In biology, the type of gamete an organism produces determines the classification of its sex.

Meiosis Type of cell division in sexually-reproducing organisms used to produce gametes

Meiosis is a special type of cell division of germ cells in sexually-reproducing organisms used to produce the gametes, such as sperm or egg cells. It involves two rounds of division that ultimately result in four cells with only one copy of each chromosome (haploid). Additionally, prior to the division, genetic material from the paternal and maternal copies of each chromosome is crossed over, creating new combinations of code on each chromosome. Later on, during fertilisation, the haploid cells produced by meiosis from a male and female will fuse to create a cell with two copies of each chromosome again, the zygote.

Ploidy Number of sets of chromosomes in a cell

Ploidy is the number of complete sets of chromosomes in a cell, and hence the number of possible alleles for autosomal and pseudoautosomal genes. Sets of chromosomes refer to the number of maternal and paternal chromosome copies, respectively, in each homologous chromosome pair, which chromosomes naturally exist as. Somatic cells, tissues, and individual organisms can be described according to the number of sets of chromosomes present : monoploid, diploid, triploid, tetraploid, pentaploid, hexaploid, heptaploid or septaploid, etc. The generic term polyploid is often used to describe cells with three or more chromosome sets.

Reproduction Biological process by which new organisms are generated from one or more parent organisms

Reproduction is the biological process by which new individual organisms – "offspring" – are produced from their "parent" or parents. Reproduction is a fundamental feature of all known life; each individual organism exists as the result of reproduction. There are two forms of reproduction: asexual and sexual.

Zygote Single diploid eukaryotic cell formed by a fertilization event between two gametes

A zygote is a eukaryotic cell formed by a fertilization event between two gametes. The zygote's genome is a combination of the DNA in each gamete, and contains all of the genetic information necessary to form a new individual organism.

Cell division Process by which living cells divide

Cell division is the process by which a parent cell divides into two or more daughter cells. Cell division usually occurs as part of a larger cell cycle. In eukaryotes, there are two distinct types of cell division; a vegetative division, whereby each daughter cell is genetically identical to the parent cell (mitosis), and a reproductive cell division, whereby the number of chromosomes in the daughter cells is reduced by half to produce haploid gametes (meiosis). In cell biology, mitosis (/maɪˈtoʊsɪs/) is a part of the cell cycle, in which, replicated chromosomes are separated into two new nuclei. Cell division gives rise to genetically identical cells in which the total number of chromosomes is maintained. In general, mitosis is preceded by the S stage of interphase and is often followed by telophase and cytokinesis; which divides the cytoplasm, organelles and cell membrane of one cell into two new cells containing roughly equal shares of these cellular components. The different stages of mitosis all together define the mitotic (M) phase of animal cell cycle—the division of the mother cell into two genetically identical daughter cells. Meiosis results in four haploid daughter cells by undergoing one round of DNA replication followed by two divisions. Homologous chromosomes are separated in the first division, and sister chromatids are separated in the second division. Both of these cell division cycles are used in the process of sexual reproduction at some point in their life cycle. Both are believed to be present in the last eukaryotic common ancestor.

Fertilisation Union of gametes of opposite sexes during the process of sexual reproduction to form a zygote

Fertilisation or fertilization, also known as generative fertilisation, syngamy and impregnation, is the fusion of gametes to give rise to a new individual organism or offspring and initiate its development. Processes such as insemination or pollination which happen before the fusion of gametes are also sometimes informally called fertilisation. The cycle of fertilisation and development of new individuals is called sexual reproduction. During double fertilisation in angiosperms the haploid male gamete combines with two haploid polar nuclei to form a triploid primary endosperm nucleus by the process of vegetative fertilisation.

Basidiomycota Division of fungi

Basidiomycota is one of two large divisions that, together with the Ascomycota, constitute the subkingdom Dikarya within the kingdom Fungi. Members are known as Basidiomycetes. More specifically, Basidiomycota includes these groups: mushrooms, puffballs, stinkhorns, bracket fungi, other polypores, jelly fungi, boletes, chanterelles, earth stars, smuts, bunts, rusts, mirror yeasts, and Cryptococcus, the human pathogenic yeast. Basidiomycota are filamentous fungi composed of hyphae and reproduce sexually via the formation of specialized club-shaped end cells called basidia that normally bear external meiospores. These specialized spores are called basidiospores. However, some Basidiomycota are obligate asexual reproducers. Basidiomycota that reproduce asexually can typically be recognized as members of this division by gross similarity to others, by the formation of a distinctive anatomical feature, cell wall components, and definitively by phylogenetic molecular analysis of DNA sequence data.

Alternation of generations Reproductive cycle of plants and algae

Alternation of generations is the type of life cycle that occurs in those plants and algae in the Archaeplastida and the Heterokontophyta that have distinct haploid sexual and diploid asexual stages. In these groups, a multicellular haploid gametophyte with n chromosomes alternates with a multicellular diploid sporophyte with 2n chromosomes, made up of n pairs. A mature sporophyte produces haploid spores by meiosis, a process which reduces the number of chromosomes to half, from 2n to n.

A somatic cell, or vegetal cell, is any biological cell forming the body of a multicellular organism other than a gamete, germ cell, gametocyte or undifferentiated stem cell.

Biological life cycle Life cycle of living species

In biology, a biological life cycle is a series of changes in form that an organism undergoes, returning to the starting state. "The concept is closely related to those of the life history, development and ontogeny, but differs from them in stressing renewal." Transitions of form may involve growth, asexual reproduction, or sexual reproduction.

Heterothallic species have sexes that reside in different individuals. The term is applied particularly to distinguish heterothallic fungi, which require two compatible partners to produce sexual spores, from homothallic ones, which are capable of sexual reproduction from a single organism.

Plasmogamy is a stage in the sexual reproduction of fungi, in which the protoplasm of two parent cells fuse without the fusion of nuclei, effectively bringing two haploid nuclei close together in the same cell. This state is followed by karyogamy, where the two nuclei fuse and then undergo meiosis to produce spores. The dikaryotic state that comes after plasmogamy will often persist for many generations before the fungi undergoes karyogamy. In lower fungi however, plasmogamy is usually immediately followed by karyogamy. A comparative genomic study indicated the presence of the machinery for plasmogamy, karyogamy and meiosis in the Amoebozoa.

Heterokaryon

A heterokaryon is a multinucleate cell that contains genetically different nuclei. Heterokaryotic and heterokaryosis are derived terms. This is a special type of syncytium. This can occur naturally, such as in the mycelium of fungi during sexual reproduction, or artificially as formed by the experimental fusion of two genetically different cells, as e.g., in hybridoma technology.

Pronucleus

A pronucleus is the nucleus of a sperm or an egg cell during the process of fertilization. The sperm cell becomes a pronucleus after the sperm enters the ovum, but before the genetic material of the sperm and egg fuse. Contrary to the sperm cell, the egg cell has a pronucleus once it becomes haploid, and not when the sperm cell arrives. Sperm and egg cells are haploid, meaning they carry half the number of chromosomes of somatic cells, so in humans, haploid cells have 23 chromosomes, while somatic cells have 46 chromosomes. The male and female pronuclei don't fuse, although their genetic material does. Instead, their membranes dissolve, leaving no barriers between the male and female chromosomes. Their chromosomes can then combine and become part of a single diploid nucleus in the resulting embryo, containing a full set of chromosomes.

An oogonium is a small diploid cell which, upon maturation, forms a primordial follicle in a female fetus or the female gametangium of certain thallophytes.

Mating in fungi Combination of genetic material between compatible mating types

Mating in fungi is a complex process governed by mating types. Research on fungal mating has focused on several model species with different behaviour. Not all fungi reproduce sexually and many that do are isogamous; thus, for many members of the fungal kingdom, the terms "male" and "female" do not apply. Homothallic species are able to mate with themselves, while in heterothallic species only isolates of opposite mating types can mate.

Sporogenesis is the production of spores in biology. The term is also used to refer to the process of reproduction via spores. Reproductive spores were found to be formed in eukaryotic organisms, such as plants, algae and fungi, during their normal reproductive life cycle. Dormant spores are formed, for example by certain fungi and algae, primarily in response to unfavorable growing conditions. Most eukaryotic spores are haploid and form through cell division, though some types are diploid or dikaryons and form through cell fusion.

Outline of cell biology Overview of and topical guide to cell biology

The following outline is provided as an overview of and topical guide to cell biology:

Sexual reproduction Reproduction process that creates a new organism by combining the genetic material of two organisms

Sexual reproduction is a type of reproduction that involves a complex life cycle in which a gamete with a single set of chromosomes (haploid) combines with another to produce a zygote that develops into an organism composed of cells with two sets of chromosomes (diploid). Sexual reproduction is the most common life cycle in multicellular eukaryotes, such as animals, fungi and plants. Sexual reproduction does not occur in prokaryotes, but they have processes with similar effects such as bacterial conjugation, transformation and transduction, which may have been precursors to sexual reproduction in early eukaryotes.

References

  1. ↑ "karyogamy". The Free Dictionary.
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  3. 1 2 3 Ni, Min; Marianna Feretzaki; Sheng Sun; Xuying Wang; Joseph Heitman (December 2011). "Sex in Fungi". Annual Review of Genetics. 45: 405–430. doi:10.1146/annurev-genet-110410-132536. PMC   3310392 . PMID   21942368.
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  5. ↑ Ünal, E.; A. Amon (2011-01-01). "Gamete Formation Resets the Aging Clock in Yeast". Cold Spring Harbor Symposia on Quantitative Biology. 76: 73–80. doi:10.1101/sqb.2011.76.011379. ISSN   0091-7451. PMC   3912942 . PMID   21890640.
  6. ↑ Guthrie, Christine; Gerald R. Fink (2004). Guide to Yeast Genetics and Molecular and Cell Biology. Gulf Professional Publishing. ISBN   9780121827786.
  7. ↑ Volk, Tom. "Tom Volk's Fungus of the Month for February 2000". Tom Volk's Fungi. University of Wisconsin-La Crosse. Retrieved 14 December 2013.
  8. ↑ Hodge, Kathie. "A fungus walks into a singles bar". Cornell Mushroom Blog. Cornell University. Retrieved 23 November 2013.
  9. ↑ Hofstatter PG, Brown MW, Lahr DJG (November 2018). "Comparative Genomics Supports Sex and Meiosis in Diverse Amoebozoa". Genome Biol Evol. 10 (11): 3118–3128. doi:10.1093/gbe/evy241. PMC   6263441 . PMID   30380054.
  10. 1 2 Molk, Jeffrey N.; E. D. Salmon; Kerry Bloom (2006-01-02). "Nuclear Congression Is Driven by Cytoplasmic Microtubule Plus End Interactions in S. cerevisiae". The Journal of Cell Biology. 172 (1): 27–39. doi:10.1083/jcb.200510032. ISSN   0021-9525. JSTOR   4134115. PMC   2063526 . PMID   16380440.
  11. 1 2 Gibeaux, Romain; Antonio Z. Politi; François Nédélec; Claude Antony; Michael Knop (2013-02-01). "Spindle pole body-anchored Kar3 drives the nucleus along microtubules from another nucleus in preparation for nuclear fusion during yeast karyogamy". Genes & Development. 27 (3): 335–349. doi:10.1101/gad.206318.112. ISSN   0890-9369. PMC   3576518 . PMID   23388829.
  12. ↑ Yamashita, Akira; Yoshihiro Fujita; Masayuki Yamamoto (2013-06-05). "Proper Microtubule Structure Is Vital for Timely Progression through Meiosis in Fission Yeast". PLOS ONE. 8 (6): e65082. Bibcode:2013PLoSO...865082Y. doi: 10.1371/journal.pone.0065082 . PMC   3673945 . PMID   23755176.
  13. ↑ Melloy, Patricia; Shu Shen; Erin White; Mark D. Rose (2009-09-01). "Distinct Roles for Key Karyogamy Proteins during Yeast Nuclear Fusion". Molecular Biology of the Cell. 20 (17): 3773–3782. doi:10.1091/mbc.E09-02-0163. ISSN   1059-1524. PMC   2735476 . PMID   19570912.
  14. ↑ Noble, Suzanne M.; Johnson, Alexander D. (December 2007). "Genetics of Candida albicans, a Diploid Human Fungal Pathogen". Annual Review of Genetics. 41 (1): 193–211. doi:10.1146/annurev.genet.41.042007.170146. PMID   17614788. S2CID   31819376.
  15. ↑ Schatten, G; Simerly, C; Schatten, H (Jun 1985). "Microtubule configurations during fertilization, mitosis, and early development in the mouse and the requirement for egg microtubule-mediated motility during mammalian fertilization". Proceedings of the National Academy of Sciences of the United States of America. 82 (12): 4152–6. Bibcode:1985PNAS...82.4152S. doi: 10.1073/pnas.82.12.4152 . PMC   397953 . PMID   3889922.
  16. ↑ Rose, Mark D.; Misra, Leanne M.; Vogel, Joseph P. (1 June 1989). "KAR2, a karyogamy gene, is the yeast homolog of the mammalian BiP/GRP78 gene". Cell. 57 (7): 1211–1221. doi: 10.1016/0092-8674(89)90058-5 . PMID   2661018.
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