A region of Ncor2 (SMRT) is replaced with a neomycin resistance gene in this targeted knockout allele. Homozygous embryos die between E13.5 and E15.5 and exhibit heart and neuronal defects.
Michael Geoff Rosenfeld, University of California, San Diego
Ncor2 (nuclear receptor co-repressor 2; SMRT) plays a critical role in forebrain development and in maintenance of the neural stem cell state.
A genomic segment including amino acids 1038-1198 of Ncor2 is replaced with a neomycin resistance gene in this targeted knockout allele. Protein expression is not detectable in mouse embryonic fibroblasts (MEFs) derived from homozygotes. Homozygous embryos die between E13.5 and E15.5 and exhibit heart and neuronal defects. These include a hypoplastic ventricular wall and a defect in ventricular septation in the heart, a defect in forebrain development, and impaired proliferation and premature differentiation of neural progenitor cells.
At E17.5, forebrain structures show a shift in the proportional volumes of dorsal and ventral telencephalon regions. A thinning of the neocortical plate is apparent throughout
both the medial and lateral regions, and extends throughout the rostro-caudal axis of the brain, extending medially to include the hippocampus. The ventro-lateral boundaries of the neocortex and the palaeocortex terminate in more dorsal positions in the brains of homozygous mutants. Axonal projections linking opposite cortical hemispheres are also significantly
altered, with both the anterior commissure and the corpus callosum exhibiting near complete
loss of volume and the hippocampal commissure also significantly reduced. Interestingly, axonal projections between the thalamus and cortex appeared more highly represented in the
homozygous knock-out brain.
While cortical progenitor cells derived from E13 homozygous knockout embryos are initially indistinguishable from wildtype cells, they exhibit impaired proliferation after 4-6 days in culture.
A genomic segment including amino acids 1038-1198 and encoding 4 exons was replaced with a rabbit β-globin/PGK-neomycin cassette via homologous recombination in (129X1/SvJ x 129S1/Sv)F1- Kitl+-derived R1 embryonic stem (ES) cells. Resultant chimeric mice were backcrossed to C57BL/6J for at least 10-15 generations.
|Allele Name||targeted mutation 1, Michael G Rosenfeld|
|Allele Type||Targeted (Null/Knockout)|
|Gene Symbol and Name||Ncor2, nuclear receptor co-repressor 2|
|Strain of Origin||(129X1/SvJ x 129S1/Sv)F1-Kitl+|
|Molecular Note||A 2 kb region containing 4 exons that encode amino acids 1038 to 1198 was replaced with a beta-globin/PGK-neo cassette. The absence of protein product was confirmed by western blot analysis.|
Heterozygotes are viable and fertile. Homozygotes are embryonic lethal at E13.5-E15.5.
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