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A sensitized mutagenesis screen identifies Gli3 as a modifier of Sox10 neurocristopathy.

Publication ,  Journal Article
Matera, I; Watkins-Chow, DE; Loftus, SK; Hou, L; Incao, A; Silver, DL; Rivas, C; Elliott, EC; Baxter, LL; Pavan, WJ
Published in: Hum Mol Genet
July 15, 2008

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.

Duke Scholars

Published In

Hum Mol Genet

DOI

EISSN

1460-2083

Publication Date

July 15, 2008

Volume

17

Issue

14

Start / End Page

2118 / 2131

Location

England

Related Subject Headings

  • Zinc Finger Protein Gli3
  • Waardenburg Syndrome
  • Transcription Factors
  • SOXE Transcription Factors
  • Repressor Proteins
  • Pigmentation
  • Neural Crest
  • Nerve Tissue Proteins
  • Mutagens
  • Mutagenesis
 

Citation

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Matera, I., Watkins-Chow, D. E., Loftus, S. K., Hou, L., Incao, A., Silver, D. L., … Pavan, W. J. (2008). A sensitized mutagenesis screen identifies Gli3 as a modifier of Sox10 neurocristopathy. Hum Mol Genet, 17(14), 2118–2131. https://doi.org/10.1093/hmg/ddn110
Matera, Ivana, Dawn E. Watkins-Chow, Stacie K. Loftus, Ling Hou, Arturo Incao, Debra L. Silver, Cecelia Rivas, Eugene C. Elliott, Laura L. Baxter, and William J. Pavan. “A sensitized mutagenesis screen identifies Gli3 as a modifier of Sox10 neurocristopathy.Hum Mol Genet 17, no. 14 (July 15, 2008): 2118–31. https://doi.org/10.1093/hmg/ddn110.
Matera I, Watkins-Chow DE, Loftus SK, Hou L, Incao A, Silver DL, et al. A sensitized mutagenesis screen identifies Gli3 as a modifier of Sox10 neurocristopathy. Hum Mol Genet. 2008 Jul 15;17(14):2118–31.
Matera, Ivana, et al. “A sensitized mutagenesis screen identifies Gli3 as a modifier of Sox10 neurocristopathy.Hum Mol Genet, vol. 17, no. 14, July 2008, pp. 2118–31. Pubmed, doi:10.1093/hmg/ddn110.
Matera I, Watkins-Chow DE, Loftus SK, Hou L, Incao A, Silver DL, Rivas C, Elliott EC, Baxter LL, Pavan WJ. A sensitized mutagenesis screen identifies Gli3 as a modifier of Sox10 neurocristopathy. Hum Mol Genet. 2008 Jul 15;17(14):2118–2131.
Journal cover image

Published In

Hum Mol Genet

DOI

EISSN

1460-2083

Publication Date

July 15, 2008

Volume

17

Issue

14

Start / End Page

2118 / 2131

Location

England

Related Subject Headings

  • Zinc Finger Protein Gli3
  • Waardenburg Syndrome
  • Transcription Factors
  • SOXE Transcription Factors
  • Repressor Proteins
  • Pigmentation
  • Neural Crest
  • Nerve Tissue Proteins
  • Mutagens
  • Mutagenesis