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Variants of the SH3 and multiple ankyrin repeat domains 3 ( SHANK3 ), which encodes postsynaptic scaffolds, are associated with brain disorders. The targeted alleles in a few  Shank3  knock-out (KO) lines contain a neomycin resistance (Neo) cassette, which may perturb the normal expression of neighboring genes; however, this has not been investigated in detail. We previously reported an unexpected increase in the mRNA expression of  Shank3  exons 1–12 in the brains of  Shank3B  KO mice generated by replacing  Shank3  exons 13–16 with the Neo cassette. In this study, we confirmed that the increased  Shank3  mRNA in  Shank3B  KO brains produced an unusual ∼60 kDa Shank3 isoform (Shank3-N), which did not properly localize to the synaptic compartment. Functionally, Shank3-N overexpression altered the dendritic spine morphology in cultured neurons. Importantly, Shank3-N expression in  Shank3B  KO mice was not a compensatory response to a reduction of full-length Shank3 because expression was still detected in the brain after normalizing the level of full-length Shank3. Moreover, in another  Shank3  KO line ( Shank3  gKO) with a similar  Shank3  exonal deletion as that in  Shank3B  KO mice but without a Neo cassette, the mRNA expression levels of  Shank3  exons 1–12 were lower than those of wild-type mice and Shank3-N was not detected in the brain. In addition, the expression levels of genes neighboring  Shank3  on chromosome 15 were altered in the striatum of  Shank3B  KO but not  Shank3  gKO mice. These results suggest that the Neo cassette has potential off-target effects in  Shank3B  KO mice.

frontiers in molecular neuroscience

The Neomycin Resistance Cassette in the Targeted Allele of Shank3B Knock-Out Mice Has Potential Off-Target Effects to Produce an Unusual Shank3 Isoform