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Genes, Volume 2, Issue 1 (March 2011), Pages 1-297

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Research

Jump to: Review

Open AccessArticle A Mutation in Mtap2 Is Associated with Arrest of Mammalian Spermatocytes before the First Meiotic Division
Genes 2011, 2(1), 21-35; doi:10.3390/genes2010021
Received: 25 October 2010 / Revised: 7 December 2010 / Accepted: 15 December 2010 / Published: 10 January 2011
Cited by 3 | PDF Full-text (378 KB) | HTML Full-text | XML Full-text
Abstract
In spite of evolutionary conservation of meiosis, many of the genes that control mammalian meiosis are still unknown. We report here that the ENU-induced repro4 mutation, identified in a screen to uncover genes that control mouse meiosis, causes failure of spermatocytes to [...] Read more.
In spite of evolutionary conservation of meiosis, many of the genes that control mammalian meiosis are still unknown. We report here that the ENU-induced repro4 mutation, identified in a screen to uncover genes that control mouse meiosis, causes failure of spermatocytes to exit meiotic prophase I via the G2/MI transition. Major events of meiotic prophase I occurred normally in affected spermatocytes and known regulators of the meiotic G2/MI transition were present and functional. Deep sequencing of mutant DNA revealed a mutation located in an intron of the Mtap2 gene, encoding microtubule-associated protein 2, and levels of Mtap2 transcript were reduced in mutant testes. This evidence implicates MTAP2 as required directly or indirectly for completion of meiosis and normal spermatogenesis in mammals. Full article
(This article belongs to the Special Issue Genetics of Mammalian Meiosis)
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Open AccessArticle Role of Polycomb Group Protein Cbx2/M33 in Meiosis Onset and Maintenance of Chromosome Stability in the Mammalian Germline
Genes 2011, 2(1), 59-80; doi:10.3390/genes2010059
Received: 30 November 2010 / Revised: 16 December 2010 / Accepted: 6 January 2011 / Published: 11 January 2011
Cited by 8 | PDF Full-text (1102 KB) | HTML Full-text | XML Full-text
Abstract
Polycomb group proteins (PcG) are major epigenetic regulators, essential for establishing heritable expression patterns of developmental control genes. The mouse PcG family member M33/Cbx2 (Chromobox homolog protein 2) is a component of the Polycomb-Repressive Complex 1 (PRC1). Targeted deletion of Cbx2/M33 in [...] Read more.
Polycomb group proteins (PcG) are major epigenetic regulators, essential for establishing heritable expression patterns of developmental control genes. The mouse PcG family member M33/Cbx2 (Chromobox homolog protein 2) is a component of the Polycomb-Repressive Complex 1 (PRC1). Targeted deletion of Cbx2/M33 in mice results in homeotic transformations of the axial skeleton, growth retardation and male-to-female sex reversal. In this study, we tested whether Cbx2 is involved in the control of chromatin remodeling processes during meiosis. Our analysis revealed sex reversal in 28.6% of  XY−/− embryos, in which a hypoplastic testis and a contralateral ovary were observed in close proximity to the kidney, while the remaining male mutant fetuses exhibited bilateral testicular hypoplasia. Notably, germ cells recovered from Cbx2(XY−/−) testes on day 18.5 of fetal development exhibited premature meiosis onset with synaptonemal complex formation suggesting a role for Cbx2 in the control of meiotic entry in male germ cells. Mutant females exhibited small ovaries with significant germ cell loss and a high proportion of oocytes with abnormal synapsis and non-homologous interactions at the pachytene stage as well as formation of univalents at diplotene. These defects were associated with failure to resolve DNA double strand breaks marked by persistent gH2AX and Rad51 foci at the late pachytene stage. Importantly, two factors required for meiotic silencing of asynapsed chromatin, ubiquitinated histone H2A (ubH2A) and the chromatin remodeling protein BRCA1, co-localized with fully synapsed chromosome axes in the majority of Cbx2(−/−) oocytes. These results provide novel evidence that Cbx2 plays a critical and previously unrecognized role in germ cell viability, meiosis onset and homologous chromosome synapsis in the mammalian germline. Full article
(This article belongs to the Special Issue Genetics of Mammalian Meiosis)
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Open AccessArticle Neutral and Non-Neutral Evolution of Duplicated Genes with Gene Conversion
Genes 2011, 2(1), 191-209; doi:10.3390/genes2010191
Received: 30 December 2010 / Revised: 20 January 2011 / Accepted: 12 February 2011 / Published: 18 February 2011
Cited by 12 | PDF Full-text (550 KB) | HTML Full-text | XML Full-text
Abstract
Gene conversion is one of the major mutational mechanisms involved in the DNA sequence evolution of duplicated genes. It contributes to create unique patters of DNA polymorphism within species and divergence between species. A typical pattern is so-called concerted evolution, in which [...] Read more.
Gene conversion is one of the major mutational mechanisms involved in the DNA sequence evolution of duplicated genes. It contributes to create unique patters of DNA polymorphism within species and divergence between species. A typical pattern is so-called concerted evolution, in which the divergence between duplicates is maintained low for a long time because of frequent exchanges of DNA fragments. In addition, gene conversion affects the DNA evolution of duplicates in various ways especially when selection operates. Here, we review theoretical models to understand the evolution of duplicates in both neutral and non-neutral cases. We also explain how these theories contribute to interpreting real polymorphism and divergence data by using some intriguing examples. Full article
(This article belongs to the Special Issue Gene Conversion in Duplicated Genes)
Open AccessArticle Hes1 Oscillations Contribute to Heterogeneous Differentiation Responses in Embryonic Stem Cells
Genes 2011, 2(1), 219-228; doi:10.3390/genes2010219
Received: 17 December 2010 / Revised: 12 February 2011 / Accepted: 13 February 2011 / Published: 22 February 2011
Cited by 7 | PDF Full-text (94 KB) | HTML Full-text | XML Full-text
Abstract
Embryonic stem (ES) cells can differentiate into multiple types of cells belonging to all three germ layers. Although ES cells are clonally established, they display heterogeneous responses upon the induction of differentiation, resulting in a mixture of various types of differentiated cells. [...] Read more.
Embryonic stem (ES) cells can differentiate into multiple types of cells belonging to all three germ layers. Although ES cells are clonally established, they display heterogeneous responses upon the induction of differentiation, resulting in a mixture of various types of differentiated cells. Our recent reports have shown that Hes1 regulates the fate choice of ES cells by repressing Notch signaling, and that the oscillatory expression of Hes1 contributes to various differentiation responses in ES cells. Here we discuss the mechanism regulating the intracellular dynamics in ES cells and how to trigger the lineage choice from pluripotent ES cells. Full article
(This article belongs to the Special Issue The Early Mouse Embryo as a Model Organism for Reprogramming)
Open AccessArticle NEK1 Facilitates Cohesin Removal during Mammalian Spermatogenesis
Genes 2011, 2(1), 260-279; doi:10.3390/genes2010260
Received: 19 January 2011 / Revised: 18 February 2011 / Accepted: 23 February 2011 / Published: 7 March 2011
Cited by 3 | PDF Full-text (1400 KB) | HTML Full-text | XML Full-text
Abstract
Meiosis is a highly conserved process, which is stringently regulated in all organisms, from fungi through to humans. Two major events define meiosis in eukaryotes. The first is the pairing, or synapsis, of homologous chromosomes and the second is the exchange of [...] Read more.
Meiosis is a highly conserved process, which is stringently regulated in all organisms, from fungi through to humans. Two major events define meiosis in eukaryotes. The first is the pairing, or synapsis, of homologous chromosomes and the second is the exchange of genetic information in a process called meiotic recombination. Synapsis is mediated by the meiosis-specific synaptonemal complex structure in combination with the cohesins that tether sister chromatids together along chromosome arms through prophase I. Previously, we identified FKBP6 as a novel component of the mammalian synaptonemal complex. Further studies demonstrated an interaction between FKBP6 and the NIMA-related kinase-1, NEK1. To further investigate the role of NEK1 in mammalian meiosis, we have examined gametogenesis in the spontaneous mutant, Nek1kat2J. Homozygous mutant animals show decreased testis size, defects in testis morphology, and in cohesin removal at late prophase I of meiosis, causing complete male infertility. Cohesin protein SMC3 remains localized to the meiotic chromosome cores at diplonema in the Nek1 mutant, and also in the related Fkbp6 mutant, while in wild type cells SMC3 is removed from the cores at the end of prophase I and becomes more diffuse throughout the DAPI stained region of the nucleus. These data implicate NEK1 as a possible kinase involved in cohesin redistribution in murine spermatocytes. Full article
(This article belongs to the Special Issue Genetics of Mammalian Meiosis)

Review

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Open AccessReview Gene Conversion in Angiosperm Genomes with an Emphasis on Genes Duplicated by Polyploidization
Genes 2011, 2(1), 1-20; doi:10.3390/genes2010001
Received: 26 November 2010 / Revised: 6 December 2010 / Accepted: 6 January 2011 / Published: 10 January 2011
Cited by 15 | PDF Full-text (492 KB) | HTML Full-text | XML Full-text
Abstract
Angiosperm genomes differ from those of mammals by extensive and recursive polyploidizations. The resulting gene duplication provides opportunities both for genetic innovation, and for concerted evolution. Though most genes may escape conversion by their homologs, concerted evolution of duplicated genes can last [...] Read more.
Angiosperm genomes differ from those of mammals by extensive and recursive polyploidizations. The resulting gene duplication provides opportunities both for genetic innovation, and for concerted evolution. Though most genes may escape conversion by their homologs, concerted evolution of duplicated genes can last for millions of years or longer after their origin. Indeed, paralogous genes on two rice chromosomes duplicated an estimated 60–70 million years ago have experienced gene conversion in the past 400,000 years. Gene conversion preserves similarity of paralogous genes, but appears to accelerate their divergence from orthologous genes in other species. The mutagenic nature of recombination coupled with the buffering effect provided by gene redundancy, may facilitate the evolution of novel alleles that confer functional innovations while insulating biological fitness of affected plants. A mixed evolutionary model, characterized by a primary birth-and-death process and occasional homoeologous recombination and gene conversion, may best explain the evolution of multigene families. Full article
(This article belongs to the Special Issue Gene Conversion in Duplicated Genes)
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Open AccessReview An Exceptional Gene: Evolution of the TSPY Gene Family in Humans and Other Great Apes
Genes 2011, 2(1), 36-47; doi:10.3390/genes2010036
Received: 24 November 2010 / Revised: 24 December 2010 / Accepted: 28 December 2010 / Published: 10 January 2011
Cited by 5 | PDF Full-text (311 KB) | HTML Full-text | XML Full-text
Abstract
The TSPY gene stands out from all other human protein-coding genes because of its high copy number and tandemly-repeated organization. Here, we review its evolutionary history in great apes in order to assess whether these unusual properties are more likely to result [...] Read more.
The TSPY gene stands out from all other human protein-coding genes because of its high copy number and tandemly-repeated organization. Here, we review its evolutionary history in great apes in order to assess whether these unusual properties are more likely to result from a relaxation of constraint or an unusual functional role. Detailed comparisons with chimpanzee are possible because a finished sequence of the chimpanzee Y chromosome is available, together with more limited data from other apes. These comparisons suggest that the human-chimpanzee ancestral Y chromosome carried a tandem array of TSPY genes which expanded on the human lineage while undergoing multiple duplication events followed by pseudogene formation on the chimpanzee lineage. The protein coding region is the most highly conserved of the multi-copy Y genes in human-chimpanzee comparisons, and the analysis of the dN/dS ratio indicates that TSPY is evolutionarily highly constrained, but may have experienced positive selection after the human-chimpanzee split. We therefore conclude that the exceptionally high copy number in humans is most likely due to a human-specific but unknown functional role, possibly involving rapid production of a large amount of TSPY protein at some stage during spermatogenesis. Full article
(This article belongs to the Special Issue The TSPY Gene Family)
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Open AccessReview Genetic Diversification by Somatic Gene Conversion
Genes 2011, 2(1), 48-58; doi:10.3390/genes2010048
Received: 21 October 2010 / Revised: 14 December 2010 / Accepted: 15 December 2010 / Published: 10 January 2011
Cited by 4 | PDF Full-text (355 KB) | HTML Full-text | XML Full-text
Abstract
Gene conversion is a type of homologous recombination that leads to transfer of genetic information among homologous DNA sequences. It can be categorized into two classes: homogenizing and diversifying gene conversions. The former class results in neutralization and homogenization of any sequence [...] Read more.
Gene conversion is a type of homologous recombination that leads to transfer of genetic information among homologous DNA sequences. It can be categorized into two classes: homogenizing and diversifying gene conversions. The former class results in neutralization and homogenization of any sequence variation among repetitive DNA sequences, and thus is important for concerted evolution. On the other hand, the latter functions to increase genetic diversity at the recombination-recipient loci. Thus, these two types of gene conversion play opposite roles in genome dynamics. Diversifying gene conversion is observed in the immunoglobulin (Ig) loci of chicken, rabbit, and other animals, and directs the diversification of Ig variable segments and acquisition of functional Ig repertoires. This type of gene conversion is initiated by the biased occurrence of recombination initiation events (e.g., DNA single- or double-strand breaks) on the recipient DNA site followed by unidirectional homologous recombination from multiple template sequences. Transcription and DNA accessibility is also important in the regulation of biased recombination initiation. In this review, we will discuss the biological significance and possible mechanisms of diversifying gene conversion in somatic cells of eukaryotes. Full article
(This article belongs to the Special Issue Gene Conversion in Duplicated Genes)
Open AccessReview Looking into the Black Box: Insights into the Mechanisms of Somatic Cell Reprogramming
Genes 2011, 2(1), 81-106; doi:10.3390/genes2010081
Received: 18 November 2010 / Revised: 22 December 2010 / Accepted: 5 January 2011 / Published: 13 January 2011
Cited by 2 | PDF Full-text (483 KB) | HTML Full-text | XML Full-text
Abstract
The dramatic discovery that somatic cells could be reprogrammed to induced pluripotent stem cells (iPSCs), by the expression of just four factors, has opened new opportunities for regenerative medicine and novel ways of modeling human diseases. Extensive research over the short time [...] Read more.
The dramatic discovery that somatic cells could be reprogrammed to induced pluripotent stem cells (iPSCs), by the expression of just four factors, has opened new opportunities for regenerative medicine and novel ways of modeling human diseases. Extensive research over the short time since the first iPSCs were generated has yielded the ability to reprogram various cell types using a diverse range of methods. However the duration, efficiency, and safety of induced reprogramming have remained a persistent limitation to achieving a robust experimental and therapeutic system. The field has worked to resolve these issues through technological advances using non-integrative approaches, factor replacement or complementation with microRNA, shRNA and drugs. Despite these advances, the molecular mechanisms underlying the reprogramming process remain poorly understood. Recently, through the use of inducible secondary reprogramming systems, researchers have now accessed more rigorous mechanistic experiments to decipher this complex process. In this review we will discuss some of the major recent findings in reprogramming, pertaining to proliferation and cellular senescence, epigenetic and chromatin remodeling, and other complex cellular processes such as morphological changes and mesenchymal-to-epithelial transition. We will focus on the implications of this work in the construction of a mechanistic understanding of reprogramming and discuss unexplored areas in this rapidly expanding field. Full article
(This article belongs to the Special Issue Natural and Induced Pluripotency in Stem Cells)
Open AccessReview Prospects and Limitations of Using Endogenous Neural Stem Cells for Brain Regeneration
Genes 2011, 2(1), 107-130; doi:10.3390/genes2010107
Received: 26 November 2010 / Revised: 6 December 2010 / Accepted: 4 January 2011 / Published: 14 January 2011
Cited by 5 | PDF Full-text (510 KB) | HTML Full-text | XML Full-text
Abstract
Neural stem cells (NSCs) are capable of producing a variety of neural cell types, and are indispensable for the development of the mammalian brain. NSCs can be induced in vitro from pluripotent stem cells, including embryonic stem cells and induced-pluripotent stem cells. [...] Read more.
Neural stem cells (NSCs) are capable of producing a variety of neural cell types, and are indispensable for the development of the mammalian brain. NSCs can be induced in vitro from pluripotent stem cells, including embryonic stem cells and induced-pluripotent stem cells. Although the transplantation of these exogenous NSCs is a potential strategy for improving presently untreatable neurological conditions, there are several obstacles to its implementation, including tumorigenic, immunological, and ethical problems. Recent studies have revealed that NSCs also reside in the adult brain. The endogenous NSCs are activated in response to disease or trauma, and produce new neurons and glia, suggesting they have the potential to regenerate damaged brain tissue while avoiding the above-mentioned problems. Here we present an overview of the possibility and limitations of using endogenous NSCs in regenerative medicine. Full article
(This article belongs to the Special Issue Natural and Induced Pluripotency in Stem Cells)
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Open AccessReview Gene Duplication and Ectopic Gene Conversion in Drosophila
Genes 2011, 2(1), 131-151; doi:10.3390/genes2010131
Received: 24 December 2010 / Revised: 26 January 2011 / Accepted: 27 February 2011 / Published: 11 February 2011
Cited by 3 | PDF Full-text (337 KB) | HTML Full-text | XML Full-text
Abstract
The evolutionary impact of gene duplication events has been a theme of Drosophila genetics dating back to the Morgan School. While considerable attention has been placed on the genetic novelties that duplicates are capable of introducing, and the role that positive selection [...] Read more.
The evolutionary impact of gene duplication events has been a theme of Drosophila genetics dating back to the Morgan School. While considerable attention has been placed on the genetic novelties that duplicates are capable of introducing, and the role that positive selection plays in their early stages of duplicate evolution, much less attention has been given to the potential consequences of ectopic (non-allelic) gene conversion on these evolutionary processes. In this paper we consider the historical origins of ectopic gene conversion models and present a synthesis of the current Drosophila data in light of several primary questions in the field. Full article
(This article belongs to the Special Issue Gene Conversion in Duplicated Genes)
Open AccessReview Meiosis in a Bottle: New Approaches to Overcome Mammalian Meiocyte Study Limitations
Genes 2011, 2(1), 152-168; doi:10.3390/genes2010152
Received: 7 December 2010 / Revised: 13 January 2011 / Accepted: 19 January 2011 / Published: 14 February 2011
Cited by 3 | PDF Full-text (317 KB) | HTML Full-text | XML Full-text
Abstract
The study of meiosis is limited because of the intrinsic nature of gametogenesis in mammals. One way to overcome these limitations would be the use of culture systems that would allow meiotic progression in vitro. There have been some attempts to [...] Read more.
The study of meiosis is limited because of the intrinsic nature of gametogenesis in mammals. One way to overcome these limitations would be the use of culture systems that would allow meiotic progression in vitro. There have been some attempts to culture mammalian meiocytes in recent years. In this review we will summarize all the efforts to-date in order to culture mammalian sperm and oocyte precursor cells. Full article
(This article belongs to the Special Issue Genetics of Mammalian Meiosis)
Open AccessReview Enlightenment of Yeast Mitochondrial Homoplasmy: Diversified Roles of Gene Conversion
Genes 2011, 2(1), 169-190; doi:10.3390/genes2010169
Received: 13 January 2011 / Revised: 18 January 2011 / Accepted: 25 January 2011 / Published: 14 February 2011
Cited by 7 | PDF Full-text (554 KB) | HTML Full-text | XML Full-text
Abstract
Mitochondria have their own genomic DNA. Unlike the nuclear genome, each cell contains hundreds to thousands of copies of mitochondrial DNA (mtDNA). The copies of mtDNA tend to have heterogeneous sequences, due to the high frequency of mutagenesis, but are quickly homogenized [...] Read more.
Mitochondria have their own genomic DNA. Unlike the nuclear genome, each cell contains hundreds to thousands of copies of mitochondrial DNA (mtDNA). The copies of mtDNA tend to have heterogeneous sequences, due to the high frequency of mutagenesis, but are quickly homogenized within a cell (“homoplasmy”) during vegetative cell growth or through a few sexual generations. Heteroplasmy is strongly associated with mitochondrial diseases, diabetes and aging. Recent studies revealed that the yeast cell has the machinery to homogenize mtDNA, using a common DNA processing pathway with gene conversion; i.e., both genetic events are initiated by a double-stranded break, which is processed into 3' single-stranded tails. One of the tails is base-paired with the complementary sequence of the recipient double-stranded DNA to form a D-loop (homologous pairing), in which repair DNA synthesis is initiated to restore the sequence lost by the breakage. Gene conversion generates sequence diversity, depending on the divergence between the donor and recipient sequences, especially when it occurs among a number of copies of a DNA sequence family with some sequence variations, such as in immunoglobulin diversification in chicken. MtDNA can be regarded as a sequence family, in which the members tend to be diversified by a high frequency of spontaneous mutagenesis. Thus, it would be interesting to determine why and how double-stranded breakage and D-loop formation induce sequence homogenization in mitochondria and sequence diversification in nuclear DNA. We will review the mechanisms and roles of mtDNA homoplasmy, in contrast to nuclear gene conversion, which diversifies gene and genome sequences, to provide clues toward understanding how the common DNA processing pathway results in such divergent outcomes. Full article
(This article belongs to the Special Issue Gene Conversion in Duplicated Genes)
Open AccessReview SET/MYND Lysine Methyltransferases Regulate Gene Transcription and Protein Activity
Genes 2011, 2(1), 210-218; doi:10.3390/genes2010210
Received: 5 January 2011 / Revised: 25 January 2011 / Accepted: 7 February 2011 / Published: 21 February 2011
Cited by 11 | PDF Full-text (366 KB) | HTML Full-text | XML Full-text
Abstract
The SET and MYND (SMYD) family of lysine methyltransferases is defined by a SET domain that is split into two segments by a MYND domain, followed by a cysteine-rich post-SET domain. While members of the SMYD family are important in the SET-mediated [...] Read more.
The SET and MYND (SMYD) family of lysine methyltransferases is defined by a SET domain that is split into two segments by a MYND domain, followed by a cysteine-rich post-SET domain. While members of the SMYD family are important in the SET-mediated regulation of gene transcription, pathological consequences have also been associated with aberrant expression of SMYD proteins. The last decade has witnessed a rapid increase in the studies and corresponding understanding of these highly impactful enzymes. Herein, we review the current body of knowledge related to the SMYD family of lysine methyltransferases and their role in transcriptional regulation, epigenetics, and tumorigenesis. Full article
Open AccessReview The Function of E-Cadherin in Stem Cell Pluripotency and Self-Renewal
Genes 2011, 2(1), 229-259; doi:10.3390/genes2010229
Received: 18 December 2010 / Revised: 11 January 2011 / Accepted: 19 January 2011 / Published: 25 February 2011
Cited by 14 | PDF Full-text (671 KB) | HTML Full-text | XML Full-text
Abstract
Embryonic stem (ES) and induced-pluripotent stem (iPS) cells can be grown indefinitely under appropriate conditions whilst retaining the ability to differentiate to cells representative of the three primary germ layers. Such cells have the potential to revolutionize medicine by offering treatment options [...] Read more.
Embryonic stem (ES) and induced-pluripotent stem (iPS) cells can be grown indefinitely under appropriate conditions whilst retaining the ability to differentiate to cells representative of the three primary germ layers. Such cells have the potential to revolutionize medicine by offering treatment options for a wide range of diseases and disorders as well as providing a model system for elucidating mechanisms involved in development and disease. In recent years, evidence for the function of E-cadherin in regulating pluripotent and self-renewal signaling pathways in ES and iPS cells has emerged. In this review, we discuss the function of E-cadherin and its interacting partners in the context of development and disease. We then describe relevant literature highlighting the function of E-cadherin in establishing and maintaining pluripotent and self-renewal properties of ES and iPS cells. In addition, we present experimental data demonstrating that exposure of human ES cells to the E-cadherin neutralizing antibody SHE78.7 allows culture of these cells in the absence of FGF2-supplemented medium. Full article
(This article belongs to the Special Issue Natural and Induced Pluripotency in Stem Cells)
Open AccessReview The Role of the Leukemia Inhibitory Factor (LIF) — Pathway in Derivation and Maintenance of Murine Pluripotent Stem Cells
Genes 2011, 2(1), 280-297; doi:10.3390/genes2010280
Received: 27 January 2011 / Revised: 26 February 2011 / Accepted: 7 March 2011 / Published: 9 March 2011
Cited by 15 | PDF Full-text (506 KB) | HTML Full-text | XML Full-text
Abstract
Developmental biology, regenerative medicine and cancer biology are more and more interested in understanding the molecular mechanisms controlling pluripotency and self-renewal in stem cells. Pluripotency is maintained by a synergistic interplay between extrinsic stimuli and intrinsic circuitries, which allow sustainment of the [...] Read more.
Developmental biology, regenerative medicine and cancer biology are more and more interested in understanding the molecular mechanisms controlling pluripotency and self-renewal in stem cells. Pluripotency is maintained by a synergistic interplay between extrinsic stimuli and intrinsic circuitries, which allow sustainment of the undifferentiated and self-renewing state. Nevertheless, even though a lot of efforts have been made in the past years, the precise mechanisms regulating these processes remain unclear. One of the key extrinsic factors is leukemia inhibitory factor (LIF) that is largely used for the cultivation and derivation of mouse embryonic and induced pluripotent stem cells. LIF acts through the LIFR/gp130 receptor and activates STAT3, an important regulator of mouse embryonic stem cell self-renewal. STAT3 is known to inhibit differentiation into both mesoderm and endoderm lineages by preventing the activation of lineage-specific differentiation programs. However, LIF activates also parallel circuitries like the PI3K-pathway and the MEK/ERK-pathway, but its mechanisms of action remain to be better elucidated. This review article aims at summarizing the actual knowledge on the importance of LIF in the maintenance of pluripotency and self-renewal in embryonic and induced pluripotent stem cells. Full article
(This article belongs to the Special Issue Natural and Induced Pluripotency in Stem Cells)

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