Kaguya was the first bimaternal mouse created in laboratory using two eggs from female parents by Tomohiro Kono and colleagues at Tokyo University of Agriculture. [1] This was a hallmark experiment as natural fertilization in mice requires the contribution of an egg from the female parent and a sperm from the male parent. The first bimaternal mouse was named after a Japanese folk tale, in which the Moon-born princess Kaguya (Kaguya-hime) is found as a baby inside a bamboo stalk.
Parthenogenesis is a form of asexual reproduction that refers to development of an embryo from an unfertilized egg cell by the female parent. Although this happens naturally in many taxa, such as plants, some invertebrates, and vertebrates, it has not been recorded in any mammals. [1] [2] Rapid advances in molecular biology and genomics have made it possible for successful artificial development of a mouse embryo solely from unfertilized eggs.
Epigenetics refers to proteins and enzymes that sit above the DNA sequence and influence its activity. Parent-specific epigenetic changes, known as genomic imprinting, are required for successful fertilization and embryonic development in mammals. [3] These modifications fine-tune the expression of key genes in development.
To overcome the genomic barriers arising due to parent-specific gene activity that prevent successful development of embryos only from egg cells in mammals, Kono and colleagues genetically modified eggs from newborn female mice to make them similar to a sperm cell. [1] Egg cells undergo DNA methylation, which is an epigenetic change associated with silencing of gene activity, during their development. Eggs from newborn mice are not methylated yet, thus making their epigenetic modifications more similar to sperm cells. They altered the expression of Igf2 and H19 genes by deleting a region of H19 in the newborn egg. [1] These two genes are key regulators of mammalian embryonic development and have different levels of activity in the sperm and egg cell due to genomic imprinting. [4] [5] The deleted region between the two contains a methylated region that regulates their activity. They then moved the nucleus of the modified newborn egg into a mature egg for artificial fertilization. [6]
Of the 598 eggs used in the experiment, only two embryos successfully developed into viable offspring. One of them was used to look at gene activity in bimaternal mice. The other was named Kaguya. Kaguya was raised to the adult stage and was able to produce offspring through mating with a male mouse.
Many of the mice pups recovered in this experiment had atypical development and died prematurely and some eggs failed to successfully impregnate female mice; only two pups survived. Mice with atypical development exhibited developmentally delayed livers. Bimaternal mice had significantly lower body and placental weight compared to the controls.
A mouse microarray, a tool used to study the activity of many genes at once, with 11’000 genes was used to compare the gene expression of the developmentally typical bimaternal mouse embryo to mice born from natural mating. This was done to see if there are any differences between the two groups at molecular level. More than 1’000 genes were found to have different levels of activity in the bimaternal mouse compared to the controls. It was revealed that these genes are mostly associated with cell communication, cell growth/maintenance, and metabolism. However, the small sample size per group, reliance on older technology, and single time point analysis may limit the informativeness of this genetic analysis.
In a follow up paper, Kono lab was able to increase the number of bimaternal mice generated by modifying the genetic manipulations performed on the newborn eggs used in the experiment. [7] Interestingly, bimaternal pups similar to controls were shown to grow at a slower rate and have a longer lifespan. [7] [4]
Genomic imprinting is an epigenetic phenomenon that causes genes to be expressed or not, depending on whether they are inherited from the female or male parent. Genes can also be partially imprinted. Partial imprinting occurs when alleles from both parents are differently expressed rather than complete expression and complete suppression of one parent's allele. Forms of genomic imprinting have been demonstrated in fungi, plants and animals. In 2014, there were about 150 imprinted genes known in mice and about half that in humans. As of 2019, 260 imprinted genes have been reported in mice and 228 in humans.
Fertilisation or fertilization, also known as generative fertilisation, syngamy and impregnation, is the fusion of gametes to give rise to a zygote and initiate its development into a new individual organism or offspring. While processes such as insemination or pollination, which happen before the fusion of gametes, are also sometimes informally referred to as fertilisation, these are technically separate processes. 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.
A maternal effect is a situation where the phenotype of an organism is determined not only by the environment it experiences and its genotype, but also by the environment and genotype of its mother. In genetics, maternal effects occur when an organism shows the phenotype expected from the genotype of the mother, irrespective of its own genotype, often due to the mother supplying messenger RNA or proteins to the egg. Maternal effects can also be caused by the maternal environment independent of genotype, sometimes controlling the size, sex, or behaviour of the offspring. These adaptive maternal effects lead to phenotypes of offspring that increase their fitness. Further, it introduces the concept of phenotypic plasticity, an important evolutionary concept. It has been proposed that maternal effects are important for the evolution of adaptive responses to environmental heterogeneity.
In biology and genetics, the germline is the population of a multicellular organism's cells that develop into germ cells. In other words, they are the cells that form gametes, which can come together to form a zygote. They differentiate in the gonads from primordial germ cells into gametogonia, which develop into gametocytes, which develop into the final gametes. This process is known as gametogenesis.
DNA methylation is a biological process by which methyl groups are added to the DNA molecule. Methylation can change the activity of a DNA segment without changing the sequence. When located in a gene promoter, DNA methylation typically acts to repress gene transcription. In mammals, DNA methylation is essential for normal development and is associated with a number of key processes including genomic imprinting, X-chromosome inactivation, repression of transposable elements, aging, and carcinogenesis.
Insulin-like growth factor 2 (IGF-2) is one of three protein hormones that share structural similarity to insulin. The MeSH definition reads: "A well-characterized neutral peptide believed to be secreted by the liver and to circulate in the blood. It has growth-regulating, insulin-like and mitogenic activities. The growth factor has a major, but not absolute, dependence on somatotropin. It is believed to be a major fetal growth factor in contrast to insulin-like growth factor 1 (IGF-1), which is a major growth factor in adults."
In biology, reprogramming refers to erasure and remodeling of epigenetic marks, such as DNA methylation, during mammalian development or in cell culture. Such control is also often associated with alternative covalent modifications of histones.
Female sperm can refer to either:
H19 is a gene for a long noncoding RNA, found in humans and elsewhere. H19 has a role in the negative regulation of body weight and cell proliferation. This gene also has a role in the formation of some cancers and in the regulation of gene expression.
PRC2 is one of the two classes of polycomb-group proteins or (PcG). The other component of this group of proteins is PRC1.
For molecular biology in mammals, DNA demethylation causes replacement of 5-methylcytosine (5mC) in a DNA sequence by cytosine (C). DNA demethylation can occur by an active process at the site of a 5mC in a DNA sequence or, in replicating cells, by preventing addition of methyl groups to DNA so that the replicated DNA will largely have cytosine in the DNA sequence.
Transgenerational epigenetic inheritance is the proposed transmission of epigenetic markers and modifications from one generation to multiple subsequent generations without altering the primary structure of DNA. Thus, the regulation of genes via epigenetic mechanisms can be heritable; the amount of transcripts and proteins produced can be altered by inherited epigenetic changes. In order for epigenetic marks to be heritable, however, they must occur in the gametes in animals, but since plants lack a definitive germline and can propagate, epigenetic marks in any tissue can be heritable.
A knockout mouse, or knock-out mouse, is a genetically modified mouse in which researchers have inactivated, or "knocked out", an existing gene by replacing it or disrupting it with an artificial piece of DNA. They are important animal models for studying the role of genes which have been sequenced but whose functions have not been determined. By causing a specific gene to be inactive in the mouse, and observing any differences from normal behaviour or physiology, researchers can infer its probable function.
Randy Jirtle is an American biologist noted for his research in epigenetics, the branch of biology that deals with inherited information that does not reside in the nucleotide sequence of DNA. Jirtle retired from Duke University, Durham, NC in 2012. He is presently Professor of Epigenetics in the Department of Biological Sciences at North Carolina State University, Raleigh, NC. Jirtle is noted for his research on genomic imprinting, and for his use of the Agouti mouse model to investigate the effect of environmental agents on the mammalian epigenome and disease susceptibility.
Wolf Reik FRS is a German-British molecular biologist and an honorary group leader at the Babraham Institute, honorary professor of Epigenetics at the University of Cambridge and associate faculty at the Wellcome Trust Sanger Institute. He was announced as the director of Altos Labs Cambridge Institute when the company launched on 19 January 2022.
Epigenetics of human development is the study of how epigenetics effects human development.
Azim Surani is a Kenyan-British developmental biologist who has been Marshall–Walton Professor at the Wellcome Trust/Cancer Research UK Gurdon Institute at the University of Cambridge since 1992, and Director of Germline and Epigenomics Research since 2013.
The TET enzymes are a family of ten-eleven translocation (TET) methylcytosine dioxygenases. They are instrumental in DNA demethylation. 5-Methylcytosine is a methylated form of the DNA base cytosine (C) that often regulates gene transcription and has several other functions in the genome.
Folami Ideraabdullah is an American geneticist and assistant professor in the Department of Genetics and the Department of Nutrition at the Gillings School of Global Public Health at the University of North Carolina at Chapel Hill. Ideraabdullah explores how maternal nutrition and environmental toxin exposure affect development through exploring epigenetic changes to DNA. She has found that maternal Vitamin D deficiencies can cause genome-wide changes in methylation patterns that persist for several generations and impact offspring health. Her international collaboration with the University of Witwatersrand represents the first time that metal levels in the placenta have been investigated in relation to birth outcomes in South Africa.
Marisa Bartolomei is an American cell biologist, the Perelman Professor of Cell and Developmental Biology and Co-Director of the Epigenetics Institute at the Perelman School of Medicine at the University of Pennsylvania. Her research considers epigenetic processes including genomic imprinting. She was elected to the National Academy of Sciences in 2021.