Drug Discovery


The C57BL/6 family tree


diagram shows the history and relationship between major B6 substrains


of the one original B6 line; however, the family has grown significantly and there is no longer a single B6 strain, but rather numerous B6 substrains, each related but with different characteristics and suit- ability for research studies. These modern B6 sub- strains are each genetically different and substrains should be considered distinct. In fact, the terms ‘B6’ or ‘C57BL/6’ are so ambiguous that their use is unadvisable as there has not been a single C57BL/6 strain for almost a century.


What is the right B6?


There are two major types of B6 mice: C57BL/6J (B6J) and C57BL/6N (B6N). The B6J substrains are all descendants from B6 mice originally main- tained at The Jackson Laboratory, whereas the B6N substrains originate from a colony established in 1951 at the National Institutes of Health using B6 mice from The Jackson Laboratory. Since 1951, these two major branches of the B6 family have diverged, each accumulating numerous genetic dif- ferences, as explained later. This B6J/B6N divide remains the greatest source of variation between the modern B6 substrains; however, there are also substantial differences between substrains of the B6J or B6N varieties. Today vendors produce genetically-defined B6J and B6N substrains that are each distinct, and spe- cific vendor codes are used to differentiate these (eg, Tac for Taconic, J for The Jackson Laboratory, Crl for Charles River and Hsd for Envigo). In some cases, several vendor codes are used for strains maintained sequentially by different vendors (eg C57BL/6NJ or C57BL/6JBomTac). When using B6 mice it is very important to reference the full nomenclature that indicates its provenance and


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vendor code (eg, C57BL/6NTac from Taconic and C57BL/6J from The Jackson Laboratory). The differences between B6 substrains is more than just semantics; not only are they genetically unique, but these attributes also affect their suit- ability for use as specific research models. In gen- eral, B6N substrains are recommended for studies addressing diabetes, metabolism, obesity and immunology, whereas B6J substrains may be more appropriate for certain behavioural assays. In some cases, potential genetic causes for these differences have been identified. Most B6J substrains have defective mitochondria due to a mutation in the Nnt gene, which may explain why B6J do not per- form as well as B6N in diabetes and obesity mod- els. Furthermore, all B6J substrains have a muta- tion in an important immune system gene, Nlrp12, which may affect their suitability as models for immunological disorders. In contrast, all B6N mice develop mild vision problems with age (Crb1 mutation) and have dysfunctional brain reward cir- cuitry (Cyfip2 mutation), making B6N mice less appropriate for certain models of neuropathology or addiction.


In addition to these major differences between the B6J and B6N substrains, individual substrains may possess other mutations that affect their per- formance. One example of a B6J strain that differs from others is C57BL/6JOlaHsd, which has a dele- tion of genes involved in neurodevelopment (Snca) and blood clotting (Mmrn1). Among the B6N, the C57BL/6NHsd substrain has impaired immune system function due to a Dock2 mutation. With such extensive variation between differ- ent B6 substrains, it is obvious that selecting a particular substrain for use should be based upon


Drug Discovery World Fall 2017


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