**4. Summary and future direction**

We have summarized the findings on *Flgft* mice revealed by four different groups (Table 1). While most of these findings were consistent with each other, there still remain several issues to be solved, for example, the influence of the genetic background and other gene mutations in these mice.


Table 1. Summary of the phenotypes of flaky tail mice

Since *Flgft* mice are not a homogenous C57BL/6 background, two papers with spontaneous eczematous skin lesion on *Flgft* mice compared their outcomes with other mouse strains, such as C57BL6 and BALB/c mice as controls (Oyoshi, et al., 2009); these two strains lie on opposite ends of the spectrum of T helper responses. Nevertheless, the skin inflammation and susceptibility to EC sensitization of non-tape stripped skin observed in *Flgft* mice were not observed in other strains. In the second paper, they observed immune responses in mice of other genotypes, such as BALB/c and C3H, as controls, but both of these lines exhibited much less severe CHS responses compared to *Flgft* mice (Moniaga, et al., 2010). These data suggested that the enhanced responses seen in *Flgft* mice were not solely due to their genetic background. In addition, other studies used the *Flgft* mice which were backcrossed four generations to a B6 strain (a background coding sequence showed 99.3% identity between B6 and *Flgft)*, and similar enhanced responses to OVA-induced AD models were observed (Fallon, et al., 2009).

Furthermore, unlike human AD patients, most of whom are heterozygous for the *FLG* mutation, the heterozygous mice intercrossed with *Flgft* mice and B6 mice did not develop spontaneous dermatitis (Moniaga, et al., 2010). Similar results were obtained with the OVA-induced AD model, where homozygous, but not heterozygous (crossed with B6 mice) *Flgft* mice, showed enhanced susceptibility to cutaneous exposure to OVA (Fallon, et al., 2009). Not only human studies but also additional mouse studies will be required to clarify these relationships.

Since *Flgft* mice express a hair phenotype (matted), one cannot eliminate the possibility that some of the observations could have been influenced by the concurrent *ma* mutation (Scharschmidt, et al., 2009). Nevertheless, one study indeed removed the matted hair allele (*ma*) early in the course of backcrossing with B6 mice, and showed enhanced antigen (OVA) ingress in mice with the same *Flg* mutation, but no *ma* mutation in their background (Fallon, et al., 2009). The effect of the *ma* mutation in relation to the *Flg*  mutation in commercially available *Flgft* mice in the development of AD-like skin lesions needs to be clarified in future studies.
