The phenotype of the taut—/— mouse suggests that disorders in osmo-lyte (shown here for taurine) transport or osmolyte deficiency may predispose to organ damage. Interestingly, liver disease also develops in heterozygous TAUT knockout (taut+/—) mice, which display near-normal taurine plasma levels (Warskulat et al., 2006b). However, defective taurine transport in heterozygotes may be unmasked in these animals upon challenges of taurine homeostasis during stress conditions.
It will be of interest to assess the phenotype of other organic osmolyte-deficient or nontransporting mouse models. Only a few organic osmolyte transporter transgene and knockout mice have been available until now. Newborn sodium/myo-inositol cotransporter (SMIT) knockout mice, which have an 84% reduction in whole body myo-inositol, die in contrast to taut— /— mice (Heller-Stilb et al., 2002) shortly after birth as a consequence of hypoventilation (Berry et al., 2003). myo-Inositol acts like taurine as an osmolyte in the brain, but SMIT is also essential for the development and function of the peripheral nerves in mice (Chau et al., 2005). Heterozygous SMIT knockout mice exhibit no neurobehavioral disturbances (Shaldubina et al., 2007). Likewise, young heterozygous TAUT knockout mice show no retinal and olfactory malfunctions in contrast to the null mutation (Heller-Stilb et al., 2002; Witt et al., 2003). However, overexpression of the smit gene in mouse lens led to an osmotic cataract (Cammarata et al., 1999; Jiang et al., 2000). Mouse models for betaine depletion or betaine transporter knockout are not yet published; however, transgenic mice have been generated that contain in their genome 2.4 kb of the 50 -flanking region of the canine betaine transporter subunit 1 gene (BGT-1) in front of a reporter gene (Kaneko etal., 1997). It was shown in these mice that this promoter region mediates an increase in transcription ofreporter gene in response to hyperosmolarity in the renal medulla.
Conditional gene knockout mice have not yet been used for studies on osmolyte transporters. Conditional gene knockout murine models have several intrinsic advantages for in vivo research compared to conventional gene knockouts, including tissue-specific and age-dependent gene knockout examinations, which may reduce lethality often seen in conventional gene knockout. Thus, further studies in conditional osmolyte transporter gene knockout mice are of great interest.
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