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closeEmbryonic lethality of SYA176 Gga2-/- mice is not due to loss of GGA2.
Posted by stuartkornfeld on 18 Dec 2013 at 15:45 GMT
In reviewing the western blots performed with brain samples from the SYA176 Gga2+/- mice (from BayGenomics/MMRRC) and the TIGM Gga2+/- mice, we realized that whereas the TIGM Gga2+/- samples expressed 50% of the wt level of GGA2, the SYA176 Gga2+/- samples consistently expressed higher levels, frequently equivalent to that of wt. This indicated that, in fact, the SYA176 strain harbors a disrupted Gga2 allele that is hypomorphic. This finding was confirmed by generating compound heterozygous mice via crossing of the SYA176 and TIGM strains in the C57Bl/6 background. The compound hets, although genetically Gga2-/-, had similar expression to TIGM Gga2+/- mice, whereas the SYA176 Gga2+/- mice had expression levels comparable to that of wt mice. These findings confirm that the SYA176 strain is hypomorphic, indicating that the SYA176 embryonic lethality is due to a mechanism independent of GGA2. The basis for this lethality is unknown at this point. Regardless, the SYA176 strain is not a valid GGA2 knock-out model.
Further analysis of TIGM Gga2-/- newborn pups confirmed that GGA2 expression is undetectable in most instances, but occasionally trace amounts of the protein were seen upon long exposure of western blots. While we cannot exclude the remote possibility that this extremely low level of expression (1-2% of wt level) might prevent embryonic lethality, it is clear that it doesn’t allow neonatal viability in the C57Bl/6 background.