References of "Balling, Rudi 50000566"
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See detailThe clinical-chemical screen in the Munich ENU Mouse Mutagenesis Project: screening for clinically relevant phenotypes.
Rathkolb, B.; Decker, T.; Fuchs, E. et al

in Mammalian Genome (2000), 11(7), 543-6

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See detailThe biochemical metabolite screen in the Munich ENU Mouse Mutagenesis Project: determination of amino acids and acylcarnitines by tandem mass spectrometry.
Rolinski, B.; Arnecke, R.; Dame, T. et al

in Mammalian Genome (2000), 11(7), 547-51

BACKGROUND: Gene mutations often result in altered protein expression and, in turn, lead to changes in metabolite levels in one or more distinct biochemical pathways. Traditional analytical methods for ... [more ▼]

BACKGROUND: Gene mutations often result in altered protein expression and, in turn, lead to changes in metabolite levels in one or more distinct biochemical pathways. Traditional analytical methods for metabolite determination are usually time consuming, expensive, and, thus, not suitable for high throughput analysis. However, recent developments in electrospray-tandem-mass-spectrometry allow comprehensive metabolite scanning from very small amounts of blood with high speed, cost effectiveness, and accuracy. METHODS: A blood spot from a filter paper equivalent to 3 microl of blood was punched out and transferred to a 96-well microtiter plate. After addition of a set of 14 stable isotope-labeled internal standards, amino acids and acylcarnitines were extracted with methanol. The dried residue was derivatized with butanolic hydrochloric acid and subjected to MSMS analysis. RESULTS: Acyl-carnitines were all determined by a precursor ion scan of 85 Da. Neutral loss scanning of 102 Da was suitable for the quantitation of threonine, serine, proline, histidine, alanine, aspartic acid, glutamic acid, methionine, tyrosine, phenylalanine, isoleucine/leucine and valine. Glycine was detected by a loss of a 56-Da fragment, whereas a 119-Da loss was suitable for the measurement of citrulline, ornithine, arginine, and lysine. Specific problems encountered: owing to their identical molecular weight, isoleucine and leucine could not be quantitated separately, and, owing to their instability, glutamine and asparagine were found to be decarboxylated to their respective acids. Determination was linear over the concentration range tested (20 to 1000 micromol/L), and intraassay and interassay coefficients of variation were in the range of 10-15%. CONCLUSION: ESI-MSMS proved to be a highly sensitive, linear, and sufficiently precise method for the quantitative determination of amino acids and acylcarnitines in mouse blood, allowing large-scale screening applications when speed and cost effectiveness are mandatory. [less ▲]

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See detailLarge-scale N-ethyl-N-nitrosourea mutagenesis of mice--from phenotypes to genes.
Rathkolb, B.; Fuchs, E.; Kolb, H. J. et al

in Experimental Physiology (2000), 85(6), 635-44

The most important tool for obtaining insight into the function of genes is the use of mutant model organisms. Homologous recombination in embryonic stem cells allows the systematic production of mouse ... [more ▼]

The most important tool for obtaining insight into the function of genes is the use of mutant model organisms. Homologous recombination in embryonic stem cells allows the systematic production of mouse mutants for any gene that has been cloned. Gene trap strategies have been designed to interrupt even unknown genes which are tagged by the inserted vector and can be characterised structurally and functionally. Complementary to such 'gene-driven' approaches, 'phenotype-driven' approaches are necessary to identify new genes or gene products through a search for mutants with specific defects, uncovering the function of genetic pathways in physiological and pathological processes. Mutagenesis using the alkylating agent N-ethyl-N-nitrosourea (ENU) is a powerful approach for the production of such mouse mutants. Since ENU induces mainly point mutations in premeiotic spermatogonia, this strategy allows the production of multiple alleles of a particular gene, which is pivotal for a fine tuned analysis of its function. [less ▲]

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See detailFrom parathyroid to thymus, via glial cells.
Balling, Rudi UL; Erben, R. G.

in Nature Medicine (2000), 6(8), 860-1

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See detailGenome-wide, large-scale production of mutant mice by ENU mutagenesis.
Hrabe de Angelis, M. H.; Flaswinkel, H.; Fuchs, H. et al

in Nature Genetics (2000), 25(4), 444-7

In the post-genome era, the mouse will have a major role as a model system for functional genome analysis. This requires a large number of mutants similar to the collections available from other model ... [more ▼]

In the post-genome era, the mouse will have a major role as a model system for functional genome analysis. This requires a large number of mutants similar to the collections available from other model organisms such as Drosophila melanogaster and Caenorhabditis elegans. Here we report on a systematic, genome-wide, mutagenesis screen in mice. As part of the German Human Genome Project, we have undertaken a large-scale ENU-mutagenesis screen for dominant mutations and a limited screen for recessive mutations. In screening over 14,000 mice for a large number of clinically relevant parameters, we recovered 182 mouse mutants for a variety of phenotypes. In addition, 247 variant mouse mutants are currently in genetic confirmation testing and will result in additional new mutant lines. This mutagenesis screen, along with the screen described in the accompanying paper, leads to a significant increase in the number of mouse models available to the scientific community. Our mutant lines are freely accessible to non-commercial users (for information, see http://www.gsf.de/ieg/groups/enu-mouse.html). [less ▲]

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See detailA mouse model for valproate teratogenicity: parental effects, homeotic transformations, and altered HOX expression.
Faiella, A.; Wernig, M.; Consalez, G. G. et al

in Human Molecular Genetics (2000), 9(2), 227-36

Valproate (VPA) is one of several effective anti-epileptic and mood-stabilizing drugs, many of which are also potent teratogens in humans and several other mammalian species. Variable teratogenicity among ... [more ▼]

Valproate (VPA) is one of several effective anti-epileptic and mood-stabilizing drugs, many of which are also potent teratogens in humans and several other mammalian species. Variable teratogenicity among inbred strains of laboratory mice suggests that genetic factors influence susceptibility. While studying the genetic basis for VPA teratogenicity in mice, we discovered that parental factors influence fetal susceptibility to induced malformations. Detailed examination of these malformations revealed that many were homeotic transformations. To test whether VPA, like retinoic acid (RA), alters HOX expression, pluripotent human embryonal carcinoma cells were treated with VPA or RA and Hox expression assessed. Altered expression of specific Hox genes may thus account for the homeotic transformations and other malformations found in VPA-treated fetuses. [less ▲]

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See detailPax1 and Pax9 synergistically regulate vertebral column development.
Peters, H.; Wilm, B.; Sakai, N. et al

in Development (1999), 126(23), 5399-408

The paralogous genes Pax1 and Pax9 constitute one group within the vertebrate Pax gene family. They encode closely related transcription factors and are expressed in similar patterns during mouse ... [more ▼]

The paralogous genes Pax1 and Pax9 constitute one group within the vertebrate Pax gene family. They encode closely related transcription factors and are expressed in similar patterns during mouse embryogenesis, suggesting that Pax1 and Pax9 act in similar developmental pathways. We have recently shown that mice homozygous for a defined Pax1 null allele exhibit morphological abnormalities of the axial skeleton, which is not affected in homozygous Pax9 mutants. To investigate a potential interaction of the two genes, we analysed Pax1/Pax9 double mutant mice. These mutants completely lack the medial derivatives of the sclerotomes, the vertebral bodies, intervertebral discs and the proximal parts of the ribs. This phenotype is much more severe than that of Pax1 single homozygous mutants. In contrast, the neural arches, which are derived from the lateral regions of the sclerotomes, are formed. The analysis of Pax9 expression in compound mutants indicates that both spatial expansion and upregulation of Pax9 expression account for its compensatory function during sclerotome development in the absence of Pax1. In Pax1/Pax9 double homozygous mutants, formation and anteroposterior polarity of sclerotomes, as well as induction of a chondrocyte-specific cell lineage, appear normal. However, instead of a segmental arrangement of vertebrae and intervertebral disc anlagen, a loose mesenchyme surrounding the notochord is formed. The gradual loss of Sox9 and Collagen II expression in this mesenchyme indicates that the sclerotomes are prevented from undergoing chondrogenesis. The first detectable defect is a low rate of cell proliferation in the ventromedial regions of the sclerotomes after sclerotome formation but before mesenchymal condensation normally occurs. At later stages, an increased number of cells undergoing apoptosis further reduces the area normally forming vertebrae and intervertebral discs. Our results reveal functional redundancy between Pax1 and Pax9 during vertebral column development and identify an early role of Pax1 and Pax9 in the control of cell proliferation during early sclerotome development. In addition, our data indicate that the development of medial and lateral elements of vertebrae is regulated by distinct genetic pathways. [less ▲]

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See detailSpatio-temporal distribution of chondromodulin-I mRNA in the chicken embryo: expression during cartilage development and formation of the heart and eye.
Dietz, U. H.; Ziegelmeier, G.; Bittner, K. et al

in Developmental Dynamics : An Official Publication of the American Association of Anatomists (1999), 216(3), 233-43

To define genes specifically expressed in cartilage and during chondrogenesis, we compared by differential display-polymerase chain reaction (DD-PCR) the mRNA populations of differentiated sternal ... [more ▼]

To define genes specifically expressed in cartilage and during chondrogenesis, we compared by differential display-polymerase chain reaction (DD-PCR) the mRNA populations of differentiated sternal chondrocytes from chicken embryos with mRNA species modulated in vitro by retinoic acid (RA). Chondrocyte-specific gene expression is downregulated by RA, and PCR-amplified cDNAs from both untreated and RA-modulated cells were differentially displayed. Amplification products only from RNA of untreated chondrocytes were further analyzed, and a cDNA-fragment of the chondromodulin-I (ChM-I) mRNA was isolated. After obtaining full length cDNA clones, we have analyzed the mRNA expression patterns at different developmental stages by RNase protection assay and in situ hybridization. Analysis of different tissues and cartilage from 17-day-old chicken embryos showed ChM-I mRNA only in chondrocytes. During somitogenesis of the chicken embryo, ChM-I transcripts were detected in the notochord, the floor and the roof plate of the neural tube, and in cartilage precursor tissues such as the sclerotomes of the somites, the developing limbs, the pharyngeal arches, the otic vesicle, and the sclera. ChM-I continued to be expressed in differentiated cartilages derived from these tissues and also in noncartilaginous domains of the developing heart and retina. Thus, in the chicken, the expression of ChM-I is not restricted to mature cartilage but is already present during early development in precartilaginous tissues as well as in heart and eye. [less ▲]

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See detailNotochord-dependent expression of MFH1 and PAX1 cooperates to maintain the proliferation of sclerotome cells during the vertebral column development.
Furumoto, T. A.; Miura, N.; Akasaka, T. et al

in Developmental Biology (1999), 210(1), 15-29

During axial skeleton development, the notochord is essential for the induction of the sclerotome and for the subsequent differentiation of cartilage forming the vertebral bodies and intervertebral discs ... [more ▼]

During axial skeleton development, the notochord is essential for the induction of the sclerotome and for the subsequent differentiation of cartilage forming the vertebral bodies and intervertebral discs. These functions are mainly mediated by the diffusible signaling molecule Sonic hedgehog. The products of the paired-box-containing Pax1 and the mesenchyme forkhead-1 (Mfh1) genes are expressed in the developing sclerotome and are essential for the normal development of the vertebral column. Here, we demonstrate that Mfh1 like Pax1 expression is dependent on Sonic hedgehog signals from the notochord, and Mfh1 and Pax1 act synergistically to generate the vertebral column. In Mfh1/Pax1 double mutants, dorsomedial structures of the vertebrae are missing, resulting in extreme spina bifida accompanied by subcutaneous myelomeningocoele, and the vertebral bodies and intervertebral discs are missing. The morphological defects in Mfh1/Pax1 double mutants strongly correlate with the reduction of the mitotic rate of sclerotome cells. Thus, both the Mfh1 and the Pax1 gene products cooperate to mediate Sonic hedgehog-dependent proliferation of sclerotome cells. [less ▲]

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See detailReliable recovery of inbred mouse lines using cryopreserved spermatozoa.
Marschall, S.; Huffstadt, U.; Balling, Rudi UL et al

in Mammalian Genome (1999), 10(8), 773-6

Since the mouse has become the most detailed model system to investigate the genetics and pathogenesis of human diseases, large numbers of new mouse strains have and continue to be produced. In nearly all ... [more ▼]

Since the mouse has become the most detailed model system to investigate the genetics and pathogenesis of human diseases, large numbers of new mouse strains have and continue to be produced. In nearly all animal facilities, the maintenance of breeding colonies is limited and mouse strains have to be archived in an efficient way. This study was undertaken to test the reliability of recovering mouse lines by use of cryopreserved spermatozoa from individual male mice. In contrast to many studies, spermatozoa and oocytes were derived from the same genetic background. 30 C3HeB/FeJ males belonging to three different categories (wild-type, F1-generation of ENU-treated males, and defined mutants) were recovered by producing at least 20 offspring from each donor. Independent of the experimental group, every single male was successfully recovered. Archiving mouse strains by cryopreservation of spermatozoa may, therefore, offer a reliable way to preserve genetically valuable mouse strains and provides an efficient management strategy for animal facilities. [less ▲]

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See detailMutation in the betaA3/A1-crystallin encoding gene Cryba1 causes a dominant cataract in the mouse.
Graw, J.; Jung, M.; Loster, J. et al

in Genomics (1999), 62(1), 67-73

During the mouse ENU mutagenesis screen, mice were tested for the occurrence of dominant cataracts. One particular mutant was discovered as a progressive opacity (Po). Heterozygotes show opacification of ... [more ▼]

During the mouse ENU mutagenesis screen, mice were tested for the occurrence of dominant cataracts. One particular mutant was discovered as a progressive opacity (Po). Heterozygotes show opacification of a superficial layer of the fetal nucleus, which progresses and finally forms a nuclear opacity. Since the homozygotes have already developed the total cataract at eye opening, the mode of inheritance is semidominant. Linkage analysis was performed using a set of genome-wide microsatellite markers. The mutation was mapped to chromosome 11 distal of the marker D11Mit242 (9.3 +/- 4.4 cM) and proximal to D11Mit36 (2.3 +/- 2.3 cM). This position makes the betaA3/A1-crystallin encoding gene Cryba1 an excellent candidate gene. Mouse Cryba1 was amplified from lens mRNA. Sequence analysis revealed a mutation of a T to an A at the second base of exon 6, leading to an exchange of Trp by Arg. Computer analysis predicts that the fourth Greek key motif of the affected betaA3/A1-crystallin will not be formed. Moreover, the mutation leads also to an additional splicing signal, to the skipping of the first 3 bp of exon 6, and finally to the deletion of the Trp residue. Both types of mRNA are present in the homozygous mutant lenses. The mutation will be referred to as Cryba1(po1). This particular mouse mutation provides an excellent animal model for a human congenital zonular cataract with suture opacities, which is caused by a mutation in the homologous gene. [less ▲]

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See detailZic1 regulates the patterning of vertebral arches in cooperation with Gli3.
Aruga, J.; Mizugishi, K.; Koseki, H. et al

in Mechanisms of Development (1999), 89(1-2), 141-50

Skeletal abnormalities are described that appeared in Zic1-deficient mice. These mice show multiple abnormalities in the axial skeleton. The deformities are severe in the dorsal parts of the vertebrae ... [more ▼]

Skeletal abnormalities are described that appeared in Zic1-deficient mice. These mice show multiple abnormalities in the axial skeleton. The deformities are severe in the dorsal parts of the vertebrae, vertebral arches, but less so in the vertebral bodies (spina bifida occulta). The proximal ribs are deformed having ectopic processes. The abnormalities found in the vertebral arches can be traced back to disturbed segmental patterns of dorsal sclerotome. The Zic1/Gli3 double mutants showed severe abnormalities of vertebral arches not found in single mutants. The abnormalities in the vertebral arches were less severe in Zic1/Pax1 mutants than Zic1/Gli3 mutants, but significantly more pronounced than in Zic1 single mutants. The three genes may act synergistically in the development of the vertebral arches. [less ▲]

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See detailOverexpression of activin A in the skin of transgenic mice reveals new activities of activin in epidermal morphogenesis, dermal fibrosis and wound repair.
Munz, B.; Smola, H.; Engelhardt, F. et al

in EMBO Journal (1999), 18(19), 5205-15

Recently we demonstrated a strong induction of activin expression after skin injury, suggesting a function of this transforming growth factor-beta family member in wound repair. To test this possibility ... [more ▼]

Recently we demonstrated a strong induction of activin expression after skin injury, suggesting a function of this transforming growth factor-beta family member in wound repair. To test this possibility, we generated transgenic mice that overexpress the activin betaA chain in the epidermis under the control of a keratin 14 promoter. The transgenic mice were significantly smaller than control littermates, and they had smaller ears and shorter tails. In their skin, the fatty tissue was replaced by connective tissue and a severe thickening of the epidermis was found. The spinous cell layer was significantly increased, and the epidermal architecture was highly disorganized. These histological abnormalities seem to result from increased proliferation of the basal keratinocytes and abnormalities in the program of keratinocyte differentiation. After skin injury, a significant enhancement of granulation tissue formation was detected in the activin-overexpressing mice, possibly as a result of premature induction of fibronectin and tenascin-C expression. These data reveal novel activities of activin in the regulation of keratinocyte proliferation and differentiation as well as in dermal fibrosis and cutaneous wound repair. [less ▲]

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See detailTailchaser (Tlc): a new mouse mutation affecting hair bundle differentiation and hair cell survival.
Kiernan, A. E.; Zalzman, M.; Fuchs, H. et al

in Journal of Neurocytology (1999), 28(10-11), 969-85

We have undertaken a phenotypic approach in the mouse to identifying molecules involved in inner ear function by N-ethyl-N-nitrosourea mutagenesis followed by screening for new dominant mutations ... [more ▼]

We have undertaken a phenotypic approach in the mouse to identifying molecules involved in inner ear function by N-ethyl-N-nitrosourea mutagenesis followed by screening for new dominant mutations affecting hearing or balance. The pathology and genetic mapping of the first of these new mutants, tailchaser (Tlc), is described here. Tlc/+ mutants display classic behavioural symptoms of a vestibular dysfunction, including head-shaking and circling. Behavioural testing of ageing mice revealed a gradual deterioration of both hearing and balance function, indicating that the pathology caused by the Tlc mutation is progressive, similar to many dominant nonsyndromic deafnesses in humans. Based on scanning electron microscopy (SEM) studies, Tlc clearly plays a developmental role in the hair cells of the cochlea since the stereocilia bundles fail to form the characteristic V-shape pattern around the time of birth. By young adult stages, Tlc/+ outer hair bundles are grossly disorganised although inner hair bundles appear relatively normal by SEM. Increased compound action potential thresholds revealed that the Tlc/+ cochlear hair cells were not functioning normally in young adults. Similar to inner hair cells, the hair bundles of the vestibular hair cells also do not appear grossly disordered. However, all types of hair cells in the Tlc/+ inner ear eventually degenerate, apparently regardless of the degree of organisation of their hair bundles. We have mapped the Tlc mutation to a 12 cM region of chromosome 2, between D2Mit164 and D2Mit423. Based on the mode of inheritance and map location, Tlc appears to be a novel mouse mutation affecting both hair cell survival and stereocilia bundle development. [less ▲]

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See detailTeeth. Where and how to make them.
Peters, H.; Balling, Rudi UL

in Trends in Genetics (1999), 15(2), 59-65

Organs have to develop at precisely determined sites to ensure functionality of the whole organism. Organogenesis is typically regulated by a series of interactions between morphologically distinct ... [more ▼]

Organs have to develop at precisely determined sites to ensure functionality of the whole organism. Organogenesis is typically regulated by a series of interactions between morphologically distinct tissues. The developing tooth of the mouse is an excellent model to study these processes and we are beginning to understand the networks regulating reciprocal tissue interactions at the molecular level. Synergistic and antagonistic effects of signaling molecules including FGFs and BMPs are recursively used to induce localized responses in the adjacent tissue layer (mesenchyme or epithelium). However, at different phases of odontogenesis these secreted growth factors have distinct effects and at the same time they are regulated by different upstream factors. The mesenchymal transcription factors Msx1 and Pax9 are initially regulated by epithelial FGFs and BMPs, but subsequently they function upstream of these signaling molecules. This cascade provides a molecular model by which reciprocal tissue interactions are controlled. [less ▲]

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See detailCadherin-11 is highly expressed in rhabdomyosarcomas and during differentiation of myoblasts in vitro.
Markus, M. A.; Reichmuth, C.; Atkinson, M. J. et al

in Journal of Pathology (1999), 187(2), 164-72

Rhabdomyosarcomas bear a morphological and genetic resemblance to developing skeletal muscle. Apart from myogenic marker genes (bHLH factors, myosin, actin), cell adhesion molecules such as N-cadherin and ... [more ▼]

Rhabdomyosarcomas bear a morphological and genetic resemblance to developing skeletal muscle. Apart from myogenic marker genes (bHLH factors, myosin, actin), cell adhesion molecules such as N-cadherin and N-CAM have been reported to be expressed both in rhabdomyosarcomas and during myogenesis. The present study demonstrates the expression of another cadherin, cadherin-11, in rhabdomyosarcomas and during differentiation of myoblasts in vitro: cadherin-11, a predominantly mesenchymal cell adhesion molecule, is highly expressed in embryonal rhabdomyosarcomas and alveolar rhabdomyosarcomas, which do not bear the Pax-3-FKHR fusion previously described. Cadherin-11 is down-regulated in normal skeletal muscle and after myotube formation in vitro. The results of this study suggest that cadherin-11 might be involved in myogenesis and that rhabdomyosarcomas may re-express or fail to down-regulate cadherin-11. Since alveolar rhabdomyosarcomas bearing the t(2;13) translocation do not express cadherin-11, it is postulated that Pax-3 and cadherin-11 might be linked and involved in the same myogenic pathway. [less ▲]

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See detailWe need more mutants: Plans for a large scale ENU mouse mutagenesis screen
Balling, Rudi UL; Hrabe de Angelis, M; Schughart, K et al

in OECD Economics Department Working Papers (1998), (98), 103-111

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See detailA locus for radiation-induced gastroschisis on mouse Chromosome 7.
Hillebrandt, S.; Streffer, C.; Montagutelli, X. et al

in Mammalian Genome (1998), 9(12), 995-7

Gastroschisis (abdominal wall defects) occurs with a high frequency in the mouse inbred strain HLG compared with C57BL/6J mice. The risk of gastroschisis increases significantly after exposure to ... [more ▼]

Gastroschisis (abdominal wall defects) occurs with a high frequency in the mouse inbred strain HLG compared with C57BL/6J mice. The risk of gastroschisis increases significantly after exposure to irradiation with X-rays during preimplantation development and follows a recessive mode of inheritance for the HLG susceptibility alleles. We have used a backcross strategy and genome-wide microsatellite typing to chromosomally map this trait. A suggestive linkage for a locus responsible for radiation-induced gastroschisis (Rigs1) was found in a region of mouse Chromosome 7. [less ▲]

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See detailWhose law for sharing research tools?
Balling, Rudi UL

in Nature (1998), 396(6711), 509

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See detailLarge scale ENU screens in the mouse: genetics meets genomics.
Hrabe de Angelis, M.; Balling, Rudi UL

in Mutation research (1998), 400(1-2), 25-32

The worldwide effort to completely sequence the human and mouse genome will be accomplished within the next years. The focus of current activities within the framework of human genome research is mainly ... [more ▼]

The worldwide effort to completely sequence the human and mouse genome will be accomplished within the next years. The focus of current activities within the framework of human genome research is mainly on the assembly of high resolution genetic and physical maps and genomic sequencing. Cloning of new genes is getting more easy using those maps. Nevertheless, it is necessary to work on a systematic analysis of gene function. Results obtained from these efforts will be of enormous value for future biological and biomedical research. However, even the complete sequence will not in all cases reveal the molecular and cellular role of the different genes. Therefore, the next phase of the Human Genome Project will have at its core the functional analysis of genes. Those genes relevant for the diagnosis, prevention and therapy of human diseases are of particular interest. Looking at the history of life sciences, mutants have been the most important tool to obtain insight into the biological function of genes. The mouse is the model of choice for the study of inherited diseases in man. In order to meet the requirements for functional human genome analysis, we need a large number of mouse mutants similar to the collection of mutants available for other model organisms such as flys and worms. To fully apply the power of genetics, multiple alleles of the same gene such as hypomorphs or hypermorphs are required. Efficient production of mouse mutants showing specific phenotypes can be achieved by the use of ethylnitrosourea (ENU). ENU is the most powerful mutagen known and we currently see a renaissance of ENU mutagenesis. The application of ENU mutagenesis is reviewed and discussed in the context of a new era of functional genomics. [less ▲]

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