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Impaired V(D)J recombination and lymphocyte development in core RAG1-expressing mice
Darryll D Dudley1, JoAnn Sekiguchi, Chengming Zhu
1Howard Hughes Medical Institute, The Children's Hospital, The Center for Blood Research, Harvard Medical School, Boston, MA 02115, USA.
The Journal of Experimental Medicine
|October 29, 2003
Summary
Core RAG1 protein retains significant in vivo function for lymphocyte development, but impairs V(D)J recombination efficiency. This suggests noncore RAG1 regions may have important roles in immune cell development.
Area of Science:
- Immunology
- Molecular Biology
Background:
- Recombination-activating gene (RAG) proteins RAG1 and RAG2 are essential for V(D)J recombination in lymphocytes.
- In vitro studies typically use truncated core RAG proteins, limiting understanding of full-length RAG1 function.
Purpose of the Study:
- To investigate the in vivo function of core RAG1 protein.
- To explore potential roles of noncore RAG1 regions in lymphocyte development and V(D)J recombination.
Main Methods:
- Generation of core RAG1 knockin (RAG1(c/c)) mice.
- Analysis of lymphocyte development, V(D)J recombination levels, and immunoglobulin heavy chain (IgH) gene rearrangements.
Main Results:
- RAG1(c/c) mice generate significant B and T cell numbers, indicating core RAG1 retains in vivo function.
- Lymphocyte development and V(D)J recombination are impaired at the progenitor stage in RAG1(c/c) mice.
- Mature B cells in RAG1(c/c) mice show persistent germline JH loci, suggesting DJH rearrangement is not strictly required for progression to VH to DJH recombination.
Conclusions:
- Core RAG1 protein possesses substantial in vivo function but is insufficient for optimal V(D)J recombination.
- Impaired lymphocyte development and recombination in RAG1(c/c) mice highlight potential roles for noncore RAG1 regions.
- Findings provide insights into the ordered assembly of immunoglobulin gene segments during V(D)J recombination.