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Renee Reijo A Pera - One of the best experts on this subject based on the ideXlab platform.
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human dazl daz and boule genes modulate primordial Germ cell and haploid gamete formation
Nature, 2009Co-Authors: Kehkooi Kee, Vanessa T Angeles, Martha Flores, Ha Nam Nguyen, Renee Reijo A PeraAbstract:Defects in Germ-cell (oocyte and sperm) development are a leading cause of infertility in men and women. Several studies have shown that Germ cells can be differentiated from mouse and human embryonic stem cells, but human Germ cells produced in this way generally fail to develop beyond the earliest stages and do not enter meiosis. Now a team from Stanford's Institute for Stem Cell Biology and Regenerative Medicine has developed a system in which primordial Germ cells can be derived from both male and female human embryonic stem cells. By silencing and overexpressing Germ-cell-specific genes, human Germ-cell formation and developmental progression can be modulated. Specifically, the human DAZL gene, which is implicated in infertility, is shown to function in primordial Germ-cell formation, whereas closely related family members, DAZ and BOULE, modulate later stages of meiosis and development of haploid male gametes. This system can be used to study Germ-cell defects and the potential to correct them therapeutically. Defects in human Germ-cell (oocyte and sperm) development are the leading cause of infertility in men and women. A Germ-cell reporter is now used to quantify and isolate primordial Germ cells derived from both male and female human embryonic stem cells. Human DAZL is observed to function in primordial Germ-cell formation, whereas the closely related genes DAZ and BOULE promote later stages of meiosis and development of gametes. The leading cause of infertility in men and women is quantitative and qualitative defects in human Germ-cell (oocyte and sperm) development. Yet, it has not been possible to examine the unique developmental genetics of human Germ-cell formation and differentiation owing to inaccessibility of Germ cells during fetal development. Although several studies have shown that Germ cells can be differentiated from mouse and human embryonic stem cells, human Germ cells differentiated in these studies generally did not develop beyond the earliest stages1,2,3,4,5,6,7,8. Here we used a Germ-cell reporter to quantify and isolate primordial Germ cells derived from both male and female human embryonic stem cells. By silencing and overexpressing genes that encode Germ-cell-specific cytoplasmic RNA-binding proteins (not transcription factors), we modulated human Germ-cell formation and developmental progression. We observed that human DAZL (deleted in azoospermia-like) functions in primordial Germ-cell formation, whereas closely related genes DAZ and BOULE (also called BOLL) promote later stages of meiosis and development of haploid gametes. These results are significant to the generation of gametes for future basic science and potential clinical applications.
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human dazl daz and boule genes modulate primordial Germ cell and haploid gamete formation
Nature, 2009Co-Authors: Kehkooi Kee, Vanessa T Angeles, Martha Flores, Ha Nam Nguyen, Renee Reijo A PeraAbstract:The leading cause of infertility in men and women is quantitative and qualitative defects in human Germ-cell (oocyte and sperm) development. Yet, it has not been possible to examine the unique developmental genetics of human Germ-cell formation and differentiation owing to inaccessibility of Germ cells during fetal development. Although several studies have shown that Germ cells can be differentiated from mouse and human embryonic stem cells, human Germ cells differentiated in these studies generally did not develop beyond the earliest stages. Here we used a Germ-cell reporter to quantify and isolate primordial Germ cells derived from both male and female human embryonic stem cells. By silencing and overexpressing genes that encode Germ-cell-specific cytoplasmic RNA-binding proteins (not transcription factors), we modulated human Germ-cell formation and developmental progression. We observed that human DAZL (deleted in azoospermia-like) functions in primordial Germ-cell formation, whereas closely related genes DAZ and BOULE (also called BOLL) promote later stages of meiosis and development of haploid gametes. These results are significant to the generation of gametes for future basic science and potential clinical applications.
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human embryonic stem cells and Germ cell development
2009Co-Authors: Nina Kossack, J Gromoll, Renee Reijo A PeraAbstract:Embryonic stem cells (ESCs) are derived from the inner cell mass (ICM) of blastocysts and are characterized by the ability to differentiate into the three primary Germ layers. Evidence shows, however, that the cells of the ICM and derived ESCs are not identical. Expression of early Germ cell–specific markers in undifferentiated ESCs and the ability of ESCs to differentiate into functional Germ cells in vitro suggest that early Germ cells and ESCs may be closely related cell types. Proteins such as Dazl, Pumilio, and Nanos are essential for specification, maintenance, and maturation of the Germ cell population and are conserved from invertebrates to vertebrates. Homologs of these RNA-binding proteins have recently been identified in human Germ cells as well as in human ESCs, suggesting a role in differentiation of ESCs towards the Germ cell lineage. This review summarizes properties of ESCs and Germ cells and highlights the importance of protein complex formation in differentiation of ESCs towards the Germ cell lineage.
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human Germ cell lineage differentiation from embryonic stem cells
CSH Protocols, 2008Co-Authors: Kehkooi Kee, Renee Reijo A PeraAbstract:INTRODUCTIONBiological and ethical constraints hinder studies of human Germ cell development despite its importance to reproductive health, including fertility and tumorigenesis. Thus, most of what we know of human Germ cell development has been extrapolated from studies in model organisms. Human embryonic stem cells (hESCs) may provide an ideal system for probing the developmental genetics of Germ cell formation and differentiation in vitro. The growth factors BMP (bone morphogenetic protein) 4, BMP7, and BMP8b are required for development of primordial Germ cells (PGCs) in mice. It has been shown that these BMPs significantly increase Germ cell differentiation from hESCs in vitro. This protocol describes a method to induce Germ cell differentiation from hESCs by the addition of BMPs to hESC differentiation medium. The protocol can be used to study the basic mechanism of Germ cell development in human cells.
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modeling human Germ cell development with embryonic stem cells
Regenerative Medicine, 2006Co-Authors: Amander T. Clark, Renee Reijo A PeraAbstract:There has previously been no robust cell-based model for examining the genetic and epigenetic mechanisms of human Germ cell formation. Human embryonic stem cells (hESCs) could potentially fill this need, as all cell types analyzed to date (including mature Germ cells) can be identified by marker analysis during hESC differentiation. Furthermore, hESCs could also be used to differentiate mature female Germ cells (oocytes) in culture as an alternate reprogramming cell for somatic cell nuclear transfer. However, to differentiate and isolate a functional Germ cell from hESCs, the mechanisms that regulate Germ cell formation need to be understood. The purpose of this review is to summarize the current understanding of the earliest events in human Germ cell formation and to describe some of the known genetic pathways that regulate Germ cell specification and development in the mouse. Finally, the current literature on the formation of Germ cells from ESCs will be described.
Cassandra G. Extavour - One of the best experts on this subject based on the ideXlab platform.
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contrasting patterns of molecular evolution in metazoan Germ line genes
BMC Evolutionary Biology, 2019Co-Authors: Carrie A. Whittle, Cassandra G. ExtavourAbstract:Germ lines are the cell lineages that give rise to the sperm and eggs in animals. The Germ lines first arise from primordial Germ cells (PGCs) during embryogenesis: these form from either a presumed derived mode of preformed Germ plasm (inheritance) or from an ancestral mechanism of inductive cell-cell signalling (induction). Numerous genes involved in Germ line specification and development have been identified and functionally studied. However, little is known about the molecular evolutionary dynamics of Germ line genes in metazoan model systems. Here, we studied the molecular evolution of Germ line genes within three metazoan model systems. These include the genus Drosophila (N=34 genes, inheritance), the fellow insect Apis (N=30, induction), and their more distant relative Caenorhabditis (N=23, inheritance). Using multiple species and established phylogenies in each genus, we report that Germ line genes exhibited marked variation in the constraint on protein sequence divergence (dN/dS) and codon usage bias (CUB) within each genus. Importantly, we found that de novo lineage-specific inheritance (LSI) genes in Drosophila (osk, pgc) and in Caenorhabditis (pie-1, pgl-1), which are essential to Germ plasm functions under the derived inheritance mode, displayed rapid protein sequence divergence relative to the other Germ line genes within each respective genus. We show this may reflect the evolution of specialized Germ plasm functions and/or low pleiotropy of LSI genes, features not shared with other Germ line genes. In addition, we observed that the relative ranking of dN/dS and of CUB between genera were each more strongly correlated between Drosophila and Caenorhabditis, from different phyla, than between Drosophila and its insect relative Apis, suggesting taxonomic differences in how Germ line genes have evolved. Taken together, the present results advance our understanding of the evolution of animal Germ line genes within three well-known metazoan models. Further, the findings provide insights to the molecular evolution of Germ line genes with respect to LSI status, pleiotropy, adaptive evolution as well as PGC-specification mode.
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Contrasting patterns of molecular evolution in metazoan Germ line genes
BMC, 2019Co-Authors: Carrie A. Whittle, Cassandra G. ExtavourAbstract:Abstract Background Germ lines are the cell lineages that give rise to the sperm and eggs in animals. The Germ lines first arise from primordial Germ cells (PGCs) during embryogenesis: these form from either a presumed derived mode of preformed Germ plasm (inheritance) or from an ancestral mechanism of inductive cell-cell signalling (induction). Numerous genes involved in Germ line specification and development have been identified and functionally studied. However, little is known about the molecular evolutionary dynamics of Germ line genes in metazoan model systems. Results Here, we studied the molecular evolution of Germ line genes within three metazoan model systems. These include the genus Drosophila (N=34 genes, inheritance), the fellow insect Apis (N=30, induction), and their more distant relative Caenorhabditis (N=23, inheritance). Using multiple species and established phylogenies in each genus, we report that Germ line genes exhibited marked variation in the constraint on protein sequence divergence (dN/dS) and codon usage bias (CUB) within each genus. Importantly, we found that de novo lineage-specific inheritance (LSI) genes in Drosophila (osk, pgc) and in Caenorhabditis (pie-1, pgl-1), which are essential to Germ plasm functions under the derived inheritance mode, displayed rapid protein sequence divergence relative to the other Germ line genes within each respective genus. We show this may reflect the evolution of specialized Germ plasm functions and/or low pleiotropy of LSI genes, features not shared with other Germ line genes. In addition, we observed that the relative ranking of dN/dS and of CUB between genera were each more strongly correlated between Drosophila and Caenorhabditis, from different phyla, than between Drosophila and its insect relative Apis, suggesting taxonomic differences in how Germ line genes have evolved. Conclusions Taken together, the present results advance our understanding of the evolution of animal Germ line genes within three well-known metazoan models. Further, the findings provide insights to the molecular evolution of Germ line genes with respect to LSI status, pleiotropy, adaptive evolution as well as PGC-specification mode
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causes and evolutionary consequences of primordial Germ cell specification mode in metazoans
Proceedings of the National Academy of Sciences of the United States of America, 2017Co-Authors: Carrie A. Whittle, Cassandra G. ExtavourAbstract:Abstract In animals, primordial Germ cells (PGCs) give rise to the Germ lines, the cell lineages that produce sperm and eggs. PGCs form in embryogenesis, typically by one of two modes: a likely ancestral mode wherein Germ cells are induced during embryogenesis by cell–cell signaling (induction) or a derived mechanism whereby Germ cells are specified by using Germ plasm—that is, maternally specified Germ-line determinants (inheritance). The causes of the shift to Germ plasm for PGC specification in some animal clades remain largely unknown, but its repeated convergent evolution raises the question of whether it may result from or confer an innate selective advantage. It has been hypothesized that the acquisition of Germ plasm confers enhanced evolvability, resulting from the release of selective constraint on somatic gene networks in embryogenesis, thus leading to acceleration of an organism’s protein-sequence evolution, particularly for genes expressed at early developmental stages, and resulting in high speciation rates in Germ plasm-containing lineages (denoted herein as the “PGC-specification hypothesis”). Although that hypothesis, if supported, could have major implications for animal evolution, our recent large-scale coding-sequence analyses from vertebrates and invertebrates provided important examples of genera that do not support the hypothesis of liberated constraint under Germ plasm. Here, we consider reasons why Germ plasm might be neither a direct target of selection nor causally linked to accelerated animal evolution. We explore alternate scenarios that could explain the repeated evolution of Germ plasm and propose potential consequences of the inheritance and induction modes to animal evolutionary biology.
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Convergent evolution of Germ granule nucleators: A hypothesis
Elsevier, 2017Co-Authors: Arpita Kulkarni, Cassandra G. ExtavourAbstract:Germ cells have been considered “the ultimate stem cell” because they alone, during normal development of sexually reproducing organisms, are able to give rise to all organismal cell types. Morphological descriptions of a specialized cytoplasm termed ‘Germ plasm’ and associated electron dense ribonucleoprotein (RNP) structures called ‘Germ granules’ within Germ cells date back as early as the 1800s. Both Germ plasm and Germ granules are implicated in Germ line specification across metazoans. However, at a molecular level, little is currently understood about the molecular mechanisms that assemble these entities in Germ cells. The discovery that in some animals, the gene products of a small number of lineage-specific genes initiate the assembly (also termed nucleation) of Germ granules and/or Germ plasm is the first step towards facilitating a better understanding of these complex biological processes. Here, we draw on research spanning over 100 years that supports the hypothesis that these nucleator genes may have evolved convergently, allowing them to perform analogous roles across animal lineages
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the transcriptional repressor blimp 1 acts downstream of bmp signaling to generate primordial Germ cells in the cricket gryllus bimaculatus
Development, 2016Co-Authors: Taro Nakamura, Cassandra G. ExtavourAbstract:Segregation of the Germ line from the soma is an essential event for transmission of genetic information across generations in all sexually reproducing animals. Although some well-studied systems such as Drosophila and Xenopus use maternally inherited Germ determinants to specify Germ cells, most animals, including mice, appear to utilize zygotic inductive cell signals to specify Germ cells during later embryogenesis. Such inductive Germ cell specification is thought to be an ancestral trait of Bilateria, but major questions remain as to the nature of an ancestral mechanism to induce Germ cells, and how that mechanism evolved. We previously reported that BMP signaling-based Germ cell induction is conserved in both the mouse Mus musculus and the cricket Gryllus bimaculatus, which is an emerging model organism for functional studies of induction-based Germ cell formation. In order to gain further insight into the functional evolution of Germ cell specification, here we examined the Gryllus ortholog of the transcription factor Blimp-1 (also known as Prdm1), which is a widely conserved bilaterian gene known to play a crucial role in the specification of Germ cells in mice. Our functional analyses of the Gryllus Blimp-1 ortholog revealed that it is essential for Gryllus primordial Germ cell development, and is regulated by upstream input from the BMP signaling pathway. This functional conservation of the epistatic relationship between BMP signaling and Blimp-1 in inductive Germ cell specification between mouse and cricket supports the hypothesis that this molecular mechanism regulated primordial Germ cell specification in a last common bilaterian ancestor.
Francesco Marchetti - One of the best experts on this subject based on the ideXlab platform.
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approaches for identifying Germ cell mutagens report of the 2013 iwgt workshop on Germ cell assays
Mutation Research-genetic Toxicology and Environmental Mutagenesis, 2015Co-Authors: Carole L Yauk, David M Demarini, Marilyn J Aardema, Ja Van Benthem, Jack Ishop, Kerry L Dearfield, Yuri E Dubrova, Masamitsu Honma, James R Lupski, Francesco MarchettiAbstract:This workshop reviewed the current science to inform and recommend the best evidence-based approaches on the use of Germ cell genotoxicity tests. The workshop questions and key outcomes were as follows. (1) Do genotoxicity and mutagenicity assays in somatic cells predict Germ cell effects? Limited data suggest that somatic cell tests detect most Germ cell mutagens, but there are strong concerns that dictate caution in drawing conclusions. (2) Should Germ cell tests be done, and when? If there is evidence that a chemical or its metabolite(s) will not reach target Germ cells or gonadal tissue, it is not necessary to conduct Germ cell tests, notwithstanding somatic outcomes. However, it was recommended that negative somatic cell mutagens with clear evidence for gonadal exposure and evidence of toxicity in Germ cells could be considered for Germ cell mutagenicity testing. For somatic mutagens that are known to reach the gonadal compartments and expose Germ cells, the chemical could be assumed to be a Germ cell mutagen without further testing. Nevertheless, Germ cell mutagenicity testing would be needed for quantitative risk assessment. (3) What new assays should be implemented and how? There is an immediate need for research on the application of whole genome sequencing in heritable mutation analysis in humans and animals, and integration of Germ cell assays with somatic cell genotoxicity tests. Focus should be on environmental exposures that can cause de novo mutations, particularly newly recognized types of genomic changes. Mutational events, which may occur by exposure of Germ cells during embryonic development, should also be investigated. Finally, where there are indications of Germ cell toxicity in repeat dose or reproductive toxicology tests, consideration should be given to leveraging those studies to inform of possible Germ cell genotoxicity.
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Approaches for identifying Germ cell mutagens: Report of the 2013 IWGT workshop on Germ cell assays(☆)
2015Co-Authors: Carole L Yauk, David M Demarini, Marilyn J Aardema, Kerry L Dearfield, Yuri E Dubrova, Masamitsu Honma, James R Lupski, J. V. Benthem, J. B. Bishop, Francesco MarchettiAbstract:This workshop reviewed the current science to inform and recommend the best evidence-based approaches on the use of Germ cell genotoxicity tests. The workshop questions and key outcomes were as follows. (1) Do genotoxicity and mutagenicity assays in somatic cells predict Germ cell effects? Limited data suggest that somatic cell tests detect most Germ cell mutagens, but there are strong concerns that dictate caution in drawing conclusions. (2) Should Germ cell tests be done, and when? If there is evidence that a chemical or its metabolite(s) will not reach target Germ cells or gonadal tissue, it is not necessary to conduct Germ cell tests, notwithstanding somatic outcomes. However, it was recommended that negative somatic cell mutagens with clear evidence for gonadal exposure and evidence of toxicity in Germ cells could be considered for Germ cell mutagenicity testing. For somatic mutagens that are known to reach the gonadal compartments and expose Germ cells, the chemical could be assumed to be a Germ cell mutagen without further testing. Nevertheless, Germ cell mutagenicity testing would be needed for quantitative risk assessment. (3) What new assays should be implemented and how? There is an immediate need for research on the application of whole genome sequencing in heritable mutation analysis in humans and animals, and integration of Germ cell assays with somatic cell genotoxicity tests. Focus should be on environmental exposures that can cause de novo mutations, particularly newly recognized types of genomic changes. Mutational events, which may occur by exposure of Germ cells during embryonic development, should also be investigated. Finally, where there are indications of Germ cell toxicity in repeat dose or reproductive toxicology tests, consideration should be given to leveraging those studies to inform of possible Germ cell genotoxicity
Holger Moch - One of the best experts on this subject based on the ideXlab platform.
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cancer testis antigen expression in testicular Germ cell tumorigenesis
Modern Pathology, 2014Co-Authors: Peter K Bode, Andrea Thielken, Simone Brandt, Andre Barghorn, Bernd Lohe, Alexander Knuth, Holger MochAbstract:Cancer testis antigens are encoded by Germ line-associated genes that are present in normal Germ cells of testis and ovary but not in differentiated tissues. Their expression in various human cancer types has been interpreted as ‘re-expression’ or as intratumoral progenitor cell signature. Cancer testis antigen expression patterns have not yet been studied in Germ cell tumorigenesis with specific emphasis on intratubular Germ cell neoplasia unclassified as a precursor lesion for testicular Germ cell tumors. Immunohistochemistry was used to study MAGEA3, MAGEA4, MAGEC1, GAGE1 and CTAG1B expression in 325 primary testicular Germ cell tumors, including 94 mixed Germ cell tumors. Seminomatous and non-seminomatous components were separately arranged and evaluated on tissue microarrays. Spermatogonia in the normal testis were positive, whereas intratubular Germ cell neoplasia unclassified was negative for all five CT antigens. Cancer testis antigen expression was only found in 3% (CTAG1B), 10% (GAGE1, MAGEA4), 33% (MAGEA3) and 40% (MAGEC1) of classic seminoma but not in non-seminomatous testicular Germ cell tumors. In contrast, all spermatocytic seminomas were positive for cancer testis antigens. These data are consistent with a different cell origin in spermatocytic seminoma compared with classic seminoma and support a progression model with loss of cancer testis antigens in early tumorigenesis of testicular Germ cell tumors and later re-expression in a subset of seminomas.
Kehkooi Kee - One of the best experts on this subject based on the ideXlab platform.
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human dazl daz and boule genes modulate primordial Germ cell and haploid gamete formation
Nature, 2009Co-Authors: Kehkooi Kee, Vanessa T Angeles, Martha Flores, Ha Nam Nguyen, Renee Reijo A PeraAbstract:Defects in Germ-cell (oocyte and sperm) development are a leading cause of infertility in men and women. Several studies have shown that Germ cells can be differentiated from mouse and human embryonic stem cells, but human Germ cells produced in this way generally fail to develop beyond the earliest stages and do not enter meiosis. Now a team from Stanford's Institute for Stem Cell Biology and Regenerative Medicine has developed a system in which primordial Germ cells can be derived from both male and female human embryonic stem cells. By silencing and overexpressing Germ-cell-specific genes, human Germ-cell formation and developmental progression can be modulated. Specifically, the human DAZL gene, which is implicated in infertility, is shown to function in primordial Germ-cell formation, whereas closely related family members, DAZ and BOULE, modulate later stages of meiosis and development of haploid male gametes. This system can be used to study Germ-cell defects and the potential to correct them therapeutically. Defects in human Germ-cell (oocyte and sperm) development are the leading cause of infertility in men and women. A Germ-cell reporter is now used to quantify and isolate primordial Germ cells derived from both male and female human embryonic stem cells. Human DAZL is observed to function in primordial Germ-cell formation, whereas the closely related genes DAZ and BOULE promote later stages of meiosis and development of gametes. The leading cause of infertility in men and women is quantitative and qualitative defects in human Germ-cell (oocyte and sperm) development. Yet, it has not been possible to examine the unique developmental genetics of human Germ-cell formation and differentiation owing to inaccessibility of Germ cells during fetal development. Although several studies have shown that Germ cells can be differentiated from mouse and human embryonic stem cells, human Germ cells differentiated in these studies generally did not develop beyond the earliest stages1,2,3,4,5,6,7,8. Here we used a Germ-cell reporter to quantify and isolate primordial Germ cells derived from both male and female human embryonic stem cells. By silencing and overexpressing genes that encode Germ-cell-specific cytoplasmic RNA-binding proteins (not transcription factors), we modulated human Germ-cell formation and developmental progression. We observed that human DAZL (deleted in azoospermia-like) functions in primordial Germ-cell formation, whereas closely related genes DAZ and BOULE (also called BOLL) promote later stages of meiosis and development of haploid gametes. These results are significant to the generation of gametes for future basic science and potential clinical applications.
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human dazl daz and boule genes modulate primordial Germ cell and haploid gamete formation
Nature, 2009Co-Authors: Kehkooi Kee, Vanessa T Angeles, Martha Flores, Ha Nam Nguyen, Renee Reijo A PeraAbstract:The leading cause of infertility in men and women is quantitative and qualitative defects in human Germ-cell (oocyte and sperm) development. Yet, it has not been possible to examine the unique developmental genetics of human Germ-cell formation and differentiation owing to inaccessibility of Germ cells during fetal development. Although several studies have shown that Germ cells can be differentiated from mouse and human embryonic stem cells, human Germ cells differentiated in these studies generally did not develop beyond the earliest stages. Here we used a Germ-cell reporter to quantify and isolate primordial Germ cells derived from both male and female human embryonic stem cells. By silencing and overexpressing genes that encode Germ-cell-specific cytoplasmic RNA-binding proteins (not transcription factors), we modulated human Germ-cell formation and developmental progression. We observed that human DAZL (deleted in azoospermia-like) functions in primordial Germ-cell formation, whereas closely related genes DAZ and BOULE (also called BOLL) promote later stages of meiosis and development of haploid gametes. These results are significant to the generation of gametes for future basic science and potential clinical applications.
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human Germ cell lineage differentiation from embryonic stem cells
CSH Protocols, 2008Co-Authors: Kehkooi Kee, Renee Reijo A PeraAbstract:INTRODUCTIONBiological and ethical constraints hinder studies of human Germ cell development despite its importance to reproductive health, including fertility and tumorigenesis. Thus, most of what we know of human Germ cell development has been extrapolated from studies in model organisms. Human embryonic stem cells (hESCs) may provide an ideal system for probing the developmental genetics of Germ cell formation and differentiation in vitro. The growth factors BMP (bone morphogenetic protein) 4, BMP7, and BMP8b are required for development of primordial Germ cells (PGCs) in mice. It has been shown that these BMPs significantly increase Germ cell differentiation from hESCs in vitro. This protocol describes a method to induce Germ cell differentiation from hESCs by the addition of BMPs to hESC differentiation medium. The protocol can be used to study the basic mechanism of Germ cell development in human cells.
