Journal Article

A sensitized mutagenesis screen identifies <i>Gli3</i> as a modifier of <i>Sox10</i> neurocristopathy

Ivana Matera, 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

in Human Molecular Genetics

Volume 17, issue 14, pages 2118-2131
Published in print July 2008 | ISSN: 0964-6906
Published online April 2008 | e-ISSN: 1460-2083 | DOI:
A sensitized mutagenesis screen identifies Gli3 as a modifier of Sox10 neurocristopathy

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Haploinsufficiency for the transcription factor SOX10 is associated with the pigmentary deficiencies of Waardenburg syndrome (WS) and is modeled in Sox10 haploinsufficient mice (Sox10LacZ/+). 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 Sox10LacZ/+ 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 (Gli3Xt-J) confirmed that a null mutation of Gli3 causes the increased hypopigmentation in Sox10LacZ/+;Gli3Mos1/+ double heterozygotes. Early melanoblast markers (Mitf, Sox10, Dct, and Si) are reduced in Gli3Mos1/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.

Journal Article.  7459 words.  Illustrated.

Subjects: Genetics and Genomics

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