A sensitized mutagenesis screen identifies Gli3 as a modifier of Sox10 neurocristopathy
Open accessAbstract
Haploinsufficiency for the transcription factor SOX10 is associated with the pigmentary deficiencies of Waardenburg syndrome (WS) and is modeled in Sox10 haploinsufficient mice (Sox10(LacZ/+)). As genetic background affects WS severity in both humans and mice, we established an N-ethyl-N-nitrosourea (ENU) mutagenesis screen to identify modifiers that increase the phenotypic severity of Sox10(LacZ/+) mice. Analysis of 230 pedigrees identified three modifiers, named modifier of Sox10 neurocristopathies (Mos1, Mos2 and Mos3). Linkage analysis confirmed their locations on mouse chromosomes 13, 4 and 3, respectively, within regions distinct from previously identified WS loci. Positional candidate analysis of Mos1 identified a truncation mutation in a hedgehog(HH)-signaling mediator, GLI-Kruppel family member 3 (Gli3). Complementation tests using a second allele of Gli3 (Gli3(Xt-J)) confirmed that a null mutation of Gli3 causes the increased hypopigmentation in Sox10(LacZ/+);Gli3(Mos1/)(+) double heterozygotes. Early melanoblast markers (Mitf, Sox10, Dct, and Si) are reduced in Gli3(Mos1/)(Mos1) embryos, indicating that loss of GLI3 signaling disrupts melanoblast specification. In contrast, mice expressing only the GLI3 repressor have normal melanoblast specification, indicating that the full-length GLI3 activator is not required for specification of neural crest to the melanocyte lineage. This study demonstrates the feasibility of sensitized screens to identify disease modifier loci and implicates GLI3 and other HH signaling components as modifiers of human neurocristopathies.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Genetic modifier screens are commonly applied to identify genes that act in developmental or biochemical pathways in fruit flies, worms, and bacteria, but this approach is rare in the mouse.
“Genetic modifier screens are commonly applied to identify genes that act in developmental or biochemical pathways in fruit flies, worms, and bacteria10; however, this approach is rare in the mouse11,12.”
From A suppressor screen in Mecp2 mutant mice implicates cholesterol metabolism in Rett syndrome (2013) · cites this paper as [12]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Wang, B., Fallon, J. F., & Beachy, P. A. (2000) · Cell · doi:10.1016/s0092-8674(00)80678-9 · Cited by 1,014 · see citing works
The transcription factor Sox10 is a key regulator of peripheral glial developmentPreprint
Britsch, S., Goerich, D. E., Riethmacher, D., Peirano, R. I., Rossner, M., Nave, K.-A., Birchmeier, C., & Wegner, M. (2001) · Genes & Development · doi:10.1101/gad.186601 · Cited by 909 · see citing works
A missense mutation of the endothelin-B receptor gene in multigenic hirschsprung's disease
Puffenberger, E. G., Hosoda, K., Washington, S. S., Nakao, K., deWit, D., Yanagisawa, M., & Chakravarti, A. (1994) · Cell · doi:10.1016/0092-8674(94)90016-7 · Cited by 883 · see citing works
SOX10 mutations in patients with Waardenburg-Hirschsprung disease
Pingault, V., Bondurand, N., Kuhlbrodt, K., Goerich, D. E., Préhu, M., Puliti, A., Herbarth, B., Hermans‐Borgmeyer, I., Legius, E., Matthijs, G., et al. (1998) · Nature Genetics · doi:10.1038/ng0298-171 · Cited by 820 · see citing works
SOX10 mutation disrupts neural crest development in Dom Hirschsprung mouse model
Southard‐Smith, E. M., Kos, L., & Pavan, W. J. (1998) · Nature Genetics · doi:10.1038/ng0198-60 · Cited by 738 · see citing works
Self-citationHui, C., & Joyner, A. L. (1993) · Nature Genetics · doi:10.1038/ng0393-241 · Cited by 707 · see citing works
Waardenburg's syndrome patients have mutations in the human homologue of the Pax-3 paired box gene
Tassabehji, M., Read, A., Newton, V., et al. (1992) · Nature · doi:10.1038/355635a0 · Cited by 699 · see citing works
Waardenburg syndrome type 2 caused by mutations in the human microphthalmia (MITF) gene
Tassabehji, M., Newton, V. E., & Read, A. (1994) · Nature Genetics · doi:10.1038/ng1194-251 · Cited by 670 · see citing works
The art and design of genetic screens: Drosophila melanogaster
St Johnston, D. (2002) · Nature Reviews Genetics · doi:10.1038/nrg751 · Cited by 644 · cited 1× · see citing works
“Historically, this type of mutagenesis screen to identify enhancers and suppressors of phenotypes has been extremely successful in lower model organisms (30) and more recently applied in mice to identify factors involved in selective biological processes (31,32).”
BackgroundGli1 is a target of Sonic hedgehog that induces ventral neural tube development
Lee, J. D., Platt, K. A., Censullo, P., & Altaba, A. R. I. (1997) · Development · doi:10.1242/dev.124.13.2537 · Cited by 633 · see citing works
Hedgehog signaling in the neural crest cells regulates the patterning and growth of facial primordiaPreprint
Jeong, J., Mao, J., Tenzen, T., Kottmann, A. H., & McMahon, A. P. (2004) · Genes & Development · doi:10.1101/gad.1190304 · Cited by 615 · see citing works
GLI3 zinc-finger gene interrupted by translocations in Greig syndrome families
Vortkamp, A., Gessler, M., & Grzeschik, K. (1991) · Nature · doi:10.1038/352539a0 · Cited by 548 · see citing works
Sonic Hedgehog-induced Activation of the Gli1Promoter Is Mediated by GLI3
Dai, P., Akimaru, H., Tanaka, Y., Maekawa, T., Nakafuku, M., & Ishii, S. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.12.8143 · Cited by 534 · see citing works
Control of neural crest cell fate by the Wnt signalling pathway
Dorsky, R. I., Moon, R. T., & Raible, D. W. (1998) · Nature · doi:10.1038/24620 · Cited by 512 · see citing works
GLI3 frameshift mutations cause autosomal dominant Pallister-Hall syndrome
Kang, S., Graham, J. M., Olney, A. H., & Biesecker, L. G. (1997) · Nature Genetics · doi:10.1038/ng0397-266 · Cited by 509 · see citing works
Strategies for mapping and cloning quantitative trait genes in rodents
Jonathan Flint, C., Valdar, W. S. J., Shifman, S., & Mott, R. (2005) · Nature Reviews Genetics · doi:10.1038/nrg1576 · Cited by 497 · see citing works
Interaction among SOX10, PAX3 and MITF, three genes altered in Waardenburg syndrome
Bondurand, N. (2000) · Human Molecular Genetics · doi:10.1093/hmg/9.13.1907 · Cited by 466 · see citing works
An exonic mutation in the HuP2 paired domain gene causes Waardenburg's syndrome
Baldwin, C. T., Hoth, C. F., Amos, J. A., et al. (1992) · Nature · doi:10.1038/355637a0 · Cited by 460 · see citing works
Edery, P., Attié‐Bitach, T., Amiel, J., et al. (1996) · Nature Genetics · doi:10.1038/ng0496-442 · Cited by 459 · see citing works
Potterf, S. B., Furumura, M., Dunn, K. J., Arnheiter, H., & Pavan, W. J. (2000) · Human Genetics · doi:10.1007/s004390000328 · Cited by 379 · see citing works
Self-citationMackenzie, M. A. F., Jordan, S. A., Budd, P. S., & Jackson, I. J. (1997) · Developmental Biology · doi:10.1006/dbio.1997.8738 · Cited by 331 · see citing works
Lineage-specific requirements of β-catenin in neural crest development
Hari, L., Brault, V., Kléber, M., et al. (2002) · The Journal of Cell Biology · doi:10.1083/jcb.200209039 · Cited by 325 · see citing works
Induction of Melanocyte-specific Microphthalmia-associated Transcription Factor by Wnt-3a
Takeda, K., Yasumoto, K., Takada, R., Takada, S., Watanabe, K., Udono, T., Saitô, H., Takahashi, K., & Shibahara, S. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.c000113200 · Cited by 322 · see citing works
Hofstra, R. M. W., Osinga, J., Tan-Sindhunata, G. M. B., et al. (1996) · Nature Genetics · doi:10.1038/ng0496-445 · Cited by 301 · see citing works
On the subspecific origin of the laboratory mouse
Yang, H., Bell, T. A., Churchill, G. A., & de Villena, F. P. (2007) · Nature Genetics · doi:10.1038/ng2087 · Cited by 299 · see citing works
Johnston, J. J., Olivos-Glander, I. M., Killoran, C., Clement, E. M., Turner, J. T., Peters, K. F., Abbott, M. H., Aughton, D. J., Aylsworth, A. S., Bamshad, M. J., et al. (2005) · The American Journal of Human Genetics · doi:10.1086/429346 · Cited by 281 · see citing works
Dorsky, R. I., Raible, D. W., & Moon, R. T. (2000) · Genes & Development · doi:10.1101/gad.14.2.158 · Cited by 279 · see citing works
Sox10 regulates the development of neural crest-derived melanocytes in Xenopus
Aoki, Y., Saint-Germain, N., Gyda, M., Magner-Fink, E., Lee, Y., Credidio, C., & Saint‐Jeannet, J. (2003) · Developmental Biology · doi:10.1016/s0012-1606(03)00161-1 · Cited by 270 · see citing works
Deletions at the SOX10 Gene Locus Cause Waardenburg Syndrome Types 2 and 4
Bondurand, N., Moal, F., Stanchina, L., et al. (2007) · The American Journal of Human Genetics · doi:10.1086/522090 · Cited by 261 · see citing works
SLUG (SNAI2) deletions in patients with Waardenburg disease
Sánchez‐Martín, M. (2002) · Human Molecular Genetics · doi:10.1093/hmg/11.25.3231 · Cited by 258 · see citing works
Gli proteins and Hedgehog signaling: development and cancer
Altaba, A. R. I. (1999) · Trends in Genetics · doi:10.1016/s0168-9525(99)01840-5 · Cited by 252 · see citing works
Mollaaghababa, R., & Pavan, W. (2003) · Oncogene · doi:10.1038/sj.onc.1206442 · Cited by 233 · see citing works
Self-citationThe roads from phenotypic variation to gene discovery: mutagenesis versus QTLs
Nadeau, J. H., & Frankel, W. N. (2000) · Nature Genetics · doi:10.1038/78051 · Cited by 213 · see citing works
Álvarez-Medina, R., Cayuso, J., Okubo, T., Takada, S., & Martı́, E. (2007) · Development · doi:10.1242/dev.012054 · Cited by 205 · see citing works
Pallister-Hall syndrome phenotype in mice mutant for Gli3
Böse, J. (2002) · Human Molecular Genetics · doi:10.1093/hmg/11.9.1129 · Cited by 189 · see citing works
Wnt and BMP Signaling Govern Lineage Segregation of Melanocytes in the Avian Embryo
Jin, E., Erickson, C. A., Takada, S., & Burrus, L. W. (2001) · Developmental Biology · doi:10.1006/dbio.2001.0222 · Cited by 183 · see citing works
Carpinelli, M. R., Hilton, D. J., Metcalf, D., Antonchuk, J. L., Hyland, C. D., Mifsud, S. L., Di Rago, L., Hilton, A. A., Willson, T. A., Roberts, A. W., et al. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0401496101 · Cited by 179 · see citing works
GLI3 encodes a 190-kilodalton protein with multiple regions of GLI similarity.
Ruppert, J. M., Vogelstein, B., Arheden, K., & Kinzler, K. W. (1990) · Molecular and Cellular Biology · doi:10.1128/mcb.10.10.5408 · Cited by 178 · see citing works
Verastegui, C., Bille, K., Ortonne, J. P., & Ballotti, R. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.c000445200 · Cited by 170 · see citing works
Lee, M., GOODALL, J. C., Verastegui, C., Ballotti, R., & Goding, C. R. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m003816200 · Cited by 165 · see citing works
The Sox10Dom Mouse: Modeling the Genetic Variation of Waardenburg-Shah (WS4) SyndromePreprint
Southard‐Smith, E. M., Angrist, M. H., Ellison, J., Agarwala, R., Baxevanis, A. D., Chakravarti, A., & Pavan, W. J. (1999) · Genome Research · doi:10.1101/gr.9.3.215 · Cited by 156 · see citing works
Self-citationPoint Mutations Throughout the GLI3 Gene Cause Greig Cephalopolysyndactyly Syndrome
Kalff-Suske, M., Wild, A., Topp, J., Wessling, M., Jacobsen, E., Bornholdt, D., Engel, H., Heuer, H., Aalfs, C. M., Ausems, M. G. E. M., et al. (1999) · Human Molecular Genetics · doi:10.1093/hmg/8.9.1769 · Cited by 147 · see citing works
Werner, T., Hammer, A., Wahlbuhl, M., Bösl, M. R., & Wegner, M. (2007) · Nucleic Acids Research · doi:10.1093/nar/gkm727 · Cited by 138 · see citing works
The emergent design of the neural tube: prepattern, SHH morphogen and GLI code
Altaba, A. R. I., Nguyên, V., & Palma, V. (2003) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2003.08.005 · Cited by 133 · see citing works
The Secreted Metalloprotease ADAMTS20 Is Required for Melanoblast Survival
Silver, D. L., Hou, L., Somerville, R. P. T., Young, M. E., Apte, S., & Pavan, W. J. (2008) · PLoS Genetics · doi:10.1371/journal.pgen.1000003 · Cited by 132 · see citing works
Self-citationMediator Modulates Gli3-Dependent Sonic Hedgehog Signaling
Zhou, H., Kim, S., Ishii, S., & Boyer, T. (2006) · Molecular and Cellular Biology · doi:10.1128/mcb.00443-06 · Cited by 121 · see citing works
Inhibitory Gli3 Activity Negatively Regulates Wnt/β-Catenin Signaling
Ulloa, F., Itasaki, N., & Briscoe, J. (2007) · Current Biology · doi:10.1016/j.cub.2007.01.062 · Cited by 113 · see citing works
Environmental signals and cell fate specification in premigratory neural crest
Dorsky, R. I., Moon, R. T., & Raible, D. W. (2000) · BioEssays · doi:10.1002/1521-1878(200008)22:8 · Cited by 111 · see citing works
Microphthalmia‐Associated Transcription Factor in the Wnt Signaling Pathway
Saitô, H., Yasumoto, K., Takeda, K., Takahashi, K., Yamamoto, H., & Shibahara, S. (2003) · Pigment Cell Research · doi:10.1034/j.1600-0749.2003.00039.x · Cited by 104 · see citing works
Patterning the Dorsal Telencephalon: A Role for Sonic Hedgehog?
Rash, B. G., & Grove, E. A. (2007) · The Journal of Neuroscience · doi:10.1523/jneurosci.3204-07.2007 · Cited by 103 · see citing works
Mouse Models for Four Types of Waardenburg Syndrome
Tachibana, M., Kobayashi, Y., & Matsushima, Y. (2003) · Pigment Cell Research · doi:10.1034/j.1600-0749.2003.00066.x · Cited by 100 · see citing works
What you can learn from one gene: GLI3
Biesecker, L. G. (2006) · Journal of Medical Genetics · doi:10.1136/jmg.2004.029181 · Cited by 93 · see citing works
colgate/hdac1 repression of foxd3 expression is required to permit mitfa-dependent melanogenesis
Ignatius, M. S., Moose, H. E., El‐Hodiri, H. M., & Henion, P. D. (2007) · Developmental Biology · doi:10.1016/j.ydbio.2007.10.045 · Cited by 81 · see citing works
Dopachrome tautomerase (Dct) regulates neural progenitor cell proliferation
Jiao, Z., Zhang, Z. G., Hornyak, T. J., Hozeska‐Solgot, A., Zhang, R. L., Wang, Y., Wang, L., Roberts, C. J., Strickland, F. M., & Chopp, M. (2006) · Developmental Biology · doi:10.1016/j.ydbio.2006.06.006 · Cited by 55 · see citing works
The Genetic Regulation of Pigment Cell Development
Silver, D. L., Hou, L., & Pavan, W. J. (2007) · Springer eBooks · doi:10.1007/978-0-387-46954-6_9 · Cited by 42 · see citing works
Self-citationRhim, H., Dunn, K., Aronzon, A., Mac, S., Cheng, M., Lamoreux, M., Tilghman, S., & Pavan, W. (2000) · Genome Research · doi:10.1101/gr.10.1.17 · Cited by 23
Self-citationA genetic screen for behavioral mutations that perturb dopaminergic homeostasis in mice
Speca, D. J., Rabbee, N., Chihara, D., Speed, T. P., & Peterson, A. S. (2005) · Genes Brain & Behavior · doi:10.1111/j.1601-183x.2005.00127.x · Cited by 18 · see citing works
Extra-toes:a new mutant gene causing multiple abnormalities in the mouse
Johnson, D. R. (1967) · Development · doi:10.1242/dev.17.3.543
Piebald lethal (sl) acts early to disrupt the development of neural crest-derived melanocytes.
Pavan, W. J., & Tilghman, S. M. (1994) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.91.15.7159
Self-citationHakami, R. M., Hou, L., Baxter, L. L., Loftus, S. K., Southard-Smith, E. M., Incao, A., Cheng, J., & Pavan, W. J. (2006) · Mechanisms of Development · doi:10.1016/j.mod.2005.11.004
Self-citationMutagenesis of the mouse germline
Justice, M. J. (1999) · Mouse Genetics and Transgenics · doi:10.1093/oso/9780199637096.003.0009
Classical Linkage Analysis and Mapping Panels
Silver, L. M. (1995) · Mouse Genetics <i>Concepts and Applications</i> · doi:10.1093/oso/9780195075540.003.0009
Cytogenetic mapping of a novel locus for type II Waardenburg syndrome
Selicorni, A., Guerneri, S., Ratti, A., & Pizzuti, A. (2002) · Human Genetics · doi:10.1007/s00439-001-0643-9
WNT1 and WNT3a promote expansion of melanocytes through distinct modes of action
Dunn, K. J., Brady, M., Ochsenbauer‐Jambor, C., Snyder, S., Incao, A., & Pavan, W. J. (2005) · Pigment Cell Research · doi:10.1111/j.1600-0749.2005.00226.x
Self-citation
Flagged first, then by citations
Research works printed but not linked: 1
- Wilkinson, D.G. and Nieto, M.A. (1993). In Wassarman, P. and DePamphilis, M. (eds), Methods in Enzymology: Guide to Techniques in Mouse Development. Academic, San Diego, pp. 361-373.
Cited by
Sorted by citations
A suppressor screen in Mecp2 mutant mice implicates cholesterol metabolism in Rett syndrome
Buchovecky, C. M., Turley, S. D., Brown, H. M., Kyle, S. M., McDonald, J. G., Liu, B., Pieper, A. A., Huang, W., Katz, D. M., Russell, D. W., et al. (2013) · Nature Genetics · doi:10.1038/ng.2714 · Cited by 234 · see citing works
Modifier genes and the plasticity of genetic networks in mice
Hamilton, B. A., & Yu, B. D. (2012) · PLoS Genetics · doi:10.1371/journal.pgen.1002644 · Cited by 78 · see citing works
- Authors
- Matera, I., Watkins-Chow, D. E., Loftus, S. K., Hou, L., Incao, A., Silver, D. L., Rivas, C., Elliott, E. C., Baxter, L. L., & Pavan, W. J.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- Pavan, William J.
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2008-04-07
- Volume
- 17
- Issue
- 14
- Pages
- 2118-2131
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- PMC
- PMC2902284
- OpenAlex
- W2135850846
- Cited by
- 60
- References
- 64
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 2 · 2023: 2 · 2021: 3 · 2020: 3 · 2019: 4 · 2018: 4 · 2017: 2 · 2016: 2 · 2015: 1 · 2014: 7 · 2013: 6 · 2012: 4
- FWCI
- 2.48
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- public-domain
- Locations
- Human Molecular Genetics (publishedVersion, public-domain)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Friedrich-Alexander-Universität Erlangen-Nürnberg
- National Institutes of Health (n01hg065403-000)
- National Human Genome Research Institute (N01 HG-65403)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (U01HD43430, U01HD043430)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › melanin and skin pigmentation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Hedgehog Signaling Pathway Studies
- Health Sciences › Medicine › Surgery › Congenital gastrointestinal and neural anomalies
- Keywords
- Gli3, Waardenburg syndrome, neurocristopathy, Hedgehog signaling, melanocyte lineage, hypopigmentation, genetic background effects
- MeSH terms
- Zinc Finger Protein Gli3, Animals, Base Sequence, Cell Differentiation, Chromosome Mapping, DNA-Binding Proteins, Embryo, Mammalian, Ethylnitrosourea, Female, Genetic Complementation Test, High Mobility Group Proteins, Humans, Male, Melanocytes, Mice, Inbred BALB C, Mice, Inbred C57BL, Mutagens, Nerve Tissue Proteins, Neural Crest, Pigmentation, Repressor Proteins, Transcription Factors, Waardenburg Syndrome, Mutagenesis, Codon, Nonsense, Gene Expression Regulation, Developmental, Mice, Kruppel-Like Transcription Factors, SOXE Transcription Factors
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
