Know Your Neighbors: Three Phenotypes in Null Mutants of the Myogenic bHLH Gene MRF4

• Published in: Cell 1996-04, Vol.85 (1), p.1-4
• Main Authors: Olson, E.N, Arnold, H.-H, Rigby, P.W.J, Wold, B.J
• Format: Article
• Language: English
• Subjects: Animals; Helix-Loop-Helix Motifs - genetics; Mice; Mice, Knockout; Mutation - genetics; Myogenic Regulatory Factors - genetics; Phenotype; Transcription Factors - genetics
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/S0092-8674(00)81073-9

The most widely used strategy for gene disruption in the mouse involves the deletion of part or all of the target gene together with concomitant insertion of a drug selection cassette, the goal being efficient creation of definitive null alleles. However, such manipulations may disrupt the expression of other genes located near the intended target and therefore confound the interpretation of phenotypes from alleles designed to be simple null mutations. A major unknown has been the frequency and severity of possible neighborhood phenotypic effects in mouse knockouts. This will presumably depend on specific aspects of long-range gene organization and cis-regulatory element function that are not known for most target genes. Recently, a very striking case of such neighborhood effects emerged from the targeted inactivation of the myogenic basic-helix-loop-helix (bHLH) gene MRF4/herculin/myf-6. The phenotypes of three different alleles of similar design were very different, ranging from complete viability of homozygotes to complete lethality. The evidence suggests that differing effects of these mutations on expression of the adjacent Myf5 gene account for much of the phenotypic variation. Here we summarize and contrast the MRF4 phenotypes, evaluate the origins of their variation, and consider other examples where similar effects may be at work. We also discuss the implications for future gene targeting experiments and suggest that these issues should be considered in the interpretation of existing knockout phenotypes.