The mouse has long been a valuable model for vision research because many spontaneous mutants affecting visual function
12 are available and additional mutations influencing the visual system can be easily isolated in genetic screens.
13 14 15 The advantages of studies in the mouse have increased with the development of transgenic mouse technology
16 and the ability to completely or conditionally delete any gene of interest.
17 18 These manipulations are usually performed with inbred strains of mice that are essentially homozygous at every genetic locus because this allows study of the manipulation in a uniform genetic background.
19 However, it is essential that unmanipulated mice from the chosen inbred strain reflect the so-called normal biology of the system tested.
Numerous inbred mouse strains harbor endogenous defects in the visual system. Many genetically isolated inbred mouse strains, including FVB/N, CBA/J, C3H/HeJ, and SWR/J, harbor the rd1 allele of the
Pde6b gene, which results in rod photoreceptor degeneration.
6 The inbred strain DBA/2J develops pigment dispersion glaucoma
20 as a result of at least two mutant loci in these animals,
21 and C57BL/6 mice are susceptible to the development of congenital microphthalmia.
22 .
Since the earliest days of the study of lens biology with transgenic mice,
23 24 FVB/N—with its fecundity and ease of oocyte microinjection
5 —has been used extensively despite the compromise in its visual function attributed to the
Pde6b rd1 mutation.
6 Here we demonstrate that inbred FVB/N mice also harbor a
Bfsp2 deletion mutation identical to that in the inbred strains 129, 101, and CBA.
8 Notably, these inbred strains do not have a known common genetic ancestor. Rather, FVB/N mice were established as an inbred strain between 1966 and 1986 at the NIH from Swiss Webster stock, which does not share any known ancestry with the 101, 129, or CBA strains that arose from ancestors maintained in William Castle’s laboratory sometime at the beginning of the 20th century.
19 This suggests that the
Bfsp2 deletion mutation arose even earlier than previously proposed
8 and that it may, like the
Pde6b mutation,
6 be present in diverse wild mouse stocks. Alternatively, this locus may be a hot spot for mutation, with the same mutation arising spontaneously multiple times in mice.
Detailed analysis of lenses from 129 strains of mice mutant for
Bfsp2 have demonstrated that they lack CP49 protein and that filensin protein levels are greatly reduced, resulting in an absence of beaded intermediate filaments.
8 9 Similarly, we demonstrate here that FVB/N lenses lack CP49 immunoreactivity and that filensin immunoreactivity is greatly reduced. Given that both the in-frame deletion of a single amino acid and the missense mutation of the
BFSP2 gene result in congenital and juvenile-onset cataract in humans,
25 26 it is apparent that beaded filament proteins are essential for lens clarity, though the lens phenotype of the functionally null
Bfsp2 mutation in mice is more subtle.
8 9 Overall, the widespread use of FVB/N in the production of transgenic mice to study lens biology suggests that some of the phenotypes reported in the literature may result from interactions between the transgenic manipulation and the underlying lack of beaded filaments.
The best inbred mouse strain for studying ocular biology is far from clear since many of the most common strains harbor mutations in genes important for ocular function. Thus, it is important to keep these underlying defects in visual function in mind when choosing which inbred strain should be used for the study of any particular research question.