Submit Data |  Help |  Video Tutorials |  News |  Publications |  FTP Download |  REST API |  Citing RGD |  Contact   

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

Authors: Matera, Ivana  Watkins-Chow, Dawn E  Loftus, Stacie K  Hou, Ling  Incao, Arturo  Silver, Debra L  Rivas, Cecelia  Elliott, Eugene C  Baxter, Laura L  Pavan, William J 
Citation: Matera I, etal., Hum Mol Genet. 2008 Jul 15;17(14):2118-31. doi: 10.1093/hmg/ddn110. Epub 2008 Apr 7.
Pubmed: (View Article at PubMed) PMID:18397875
DOI: Full-text: DOI:10.1093/hmg/ddn110

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.

Annotation

Disease Annotations
Objects Annotated

Additional Information

 
CRRD Object Information
CRRD ID: 12738207
Created: 2017-01-30
Species: All species
Last Modified: 2017-01-30
Status: ACTIVE



NHLBI Logo

RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.