A novel intergenic ETnII-β insertion mutation causes multiple malformations in polypodia mice
Jessica A Lehoczky1, Peedikayil E Thomas, Kevin M Patrie
1Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, United States of America.
Plos Genetics
|December 17, 2013
Summary
A novel early transposon insertion causes the Polypodia mutation in mice, leading to developmental defects and altered gene expression. This transposon disrupts normal development by upregulating Dusp9 during early embryogenesis.
Area of Science:
- Developmental Biology
- Genetics
- Molecular Biology
Background:
- Early transposon (ETn) insertions cause approximately 10% of spontaneous mouse mutations.
- The Polypodia (Ppd) mutation, an X-linked dominant mutation, causes significant body plan morphogenesis defects.
Purpose of the Study:
- To identify the molecular cause of the Polypodia (Ppd) mutation.
- To investigate the mechanism by which the Ppd mutation affects gene expression and development.
Main Methods:
- Genetic mapping to refine the Ppd mutation interval.
- Identification of a novel ETnII-β transposon insertion.
- Generation of knock-in mice to validate the transposon's role.
- Comparison of gene expression in wild-type and mutant embryonic stem (ES) cells.
Main Results:
- A novel ETnII-β transposon insertion was identified 1.6 kb downstream of Dusp9.
- Knock-in mice with the ETn insertion exhibited Ppd phenotypes, confirming the insertion as the causative lesion.
- Mutant ES cells showed significant upregulation of Dusp9 mRNA and protein.
Conclusions:
- The Ppd mutation is caused by an intergenic ETn insertion.
- This insertion dysregulates nearby gene expression, specifically upregulating Dusp9, during early development.
- The findings highlight the role of transposon insertions in causing complex developmental phenotypes.
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