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Synpolydactyly in mice with a targeted deficiency in the HoxD complex
1Department of Zoology and Animal Biology, University of Geneva, Sciences III, Switzerland.
Nature
|November 7, 1996
Summary
Simultaneously inactivating Hoxd-11, Hoxd-12, and Hoxd-13 genes in mice disrupts digit development, causing skeletal defects. This research offers insights into human synpolydactyly and the functional hierarchy of Hoxd genes.
Area of Science:
- Developmental Biology
- Genetics
- Molecular Biology
Background:
- Mammalian digit morphogenesis relies on the HoxD gene complex during limb bud development.
- Understanding the specific roles of HoxD genes is crucial for deciphering limb malformations.
Purpose of the Study:
- To investigate the combined function of Hoxd-11, Hoxd-12, and Hoxd-13 genes in mammalian digit development.
- To establish an animal model for studying human digit malformations like synpolydactyly.
Main Methods:
- Utilized embryonic stem (ES) cells and a loxP/Cre site-specific recombination system to create a triple gene deficiency.
- Generated mice homozygous for the deficiency, eliminating Hoxd-11, Hoxd-12, and Hoxd-13 gene products.
- Incorporated a Hoxd-11/lacZ reporter gene to track cellular effects of the triple inactivation.
Main Results:
- Mice with the triple deficiency exhibited underdeveloped digit primordia.
- Observed disorganized cartilage patterns and impaired skeletal mass in the affected mice.
- The observed defects closely resemble those seen in human synpolydactyly.
Conclusions:
- The simultaneous loss of Hoxd-11, Hoxd-12, and Hoxd-13 function leads to significant digit malformations.
- Human synpolydactyly, linked to HOXD13 mutations, may result from the loss of function of multiple Hoxd genes.
- These findings reveal a functional hierarchy among these Hoxd genes and provide a valuable model for studying human digit malformations.
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