Dissertation/Thesis Abstract

Extra-toes spotting (Xs): A genetic characterization of a mouse mutant exhibiting developmental malformations and disruption in sonic hedgehog signaling
by Gildea, Derek E., Ph.D., The George Washington University, 2009, 140; 3359741
Abstract (Summary)

The Sonic hedgehog signaling pathway regulates many developmental processes, including limb patterning and digit specification. Dysregulation of this pathway can result in developmental malformation, as evidenced in Greig cephalopolysyndactyly syndrome (GCPS). One genetic cause for GCPS is the mutation of the Glioma-associated oncogene-3 (GLI3) gene, which encodes a transcription factor that operates downstream of the Sonic hedgehog (SHH) ligand. However, ∼15% of patients diagnosed with GCPS have no detectable mutations in GLI3. GCPS is a rare disease and often occurs sporadically, making human linkage mapping for other GCPS genes impossible. Therefore, to find additional genes responsible for GCPS, we chose to identify polydactylous mouse mutants as potential animal models for GCPS. Extra-toes spotting (Xs) was selected since the Xs phenotype is highly similar to the Extra-toes (Gli3Xt) mouse. Gli3Xt is a known animal model for GCPS. Both mice exhibit preaxial polydactyly and ventral hypopigmentation, along with the less penetrant manifestation of shortening of forelimb long bones. Previous mapping excluded mouse Gli3 as the gene mutated in XsJ (Jackson allele) mice. We performed linkage mapping to further narrow the Xs interval, and sequencing of genes in our refined critical region enabled us to identify a point mutation (c.906C>T) in the Eukaryotic translation initiation factor 3-subunit C (Eif3c) that creates a premature stop codon. Mutation of Eif3c was confirmed as causative for the Xs phenotype with the identification of a 57 nucleotide deletion in Eif3c (c.1761_1817del) found in another Xs allele, Extra-toes spotting like (Xsl). Eif3c is one of 13 subunits of Eif3, and is considered a core subunit necessary for Eif3 function. Eif3 aids in the recruitment of Met-tRNAiMet and mRNA to the 40S ribosome and scanning for the start codon during translation initiation. Considering Gli3 Xt and Xs mice show considerable phenotypic overlap, we hypothesized that mutation of Eif3c affects Shh/Gli3 signaling. To test this hypothesis, we used in situ hybridization to evaluate in XsJ/+ embryos the expression of genes in the Shh/Gli3 pathway. Data show misexpression of Shh, Ptch1, Fgf8, Gli1, and Hoxd13, suggesting that Eif3c has an effect on the Shh/Gli3 pathway.

Indexing (document details)
Advisor: Biesecker, Leslie G., Chiaramello, Anne E.
Commitee: Moody, Sally A., Pavan, William J., Stepp, Mary Ann
School: The George Washington University
Department: Biomedical Sciences
School Location: United States -- District of Columbia
Source: DAI-B 70/06, Dissertation Abstracts International
Source Type: DISSERTATION
Subjects: Genetics
Keywords: Developmental malformations, Greig cephalopolysyndactyly syndrome
Publication Number: 3359741
ISBN: 9781109219920
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