Proceedings of The Japanese Society of Animal Models for Human Diseases
Online ISSN : 1884-4197
Print ISSN : 0918-8991
ISSN-L : 0918-8991
Patho-Physiology of Myelin Deficient Mice
Ken-ichi YAMAMURAZhenghua LIYuichi OIKE
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2006 Volume 22 Pages 47-53


Mouse models for human diseases have been shown to be very useful for analyzing patho-physiology of disease development and devising a new way of treatment including drug development. In this review, we will demonstrate this by two examples.
Among several spontaneous mutants showing tremor, the quaking viable (qkv) mutation is an autosomal recessive mutation that exhibits pleiotropic effects on myelination and spermatogenesis (male sterility) . Homozygous mutant animals exhibit a characteristic tremor or ‘quaking’ of the hindlimbs by postnatal 10 day, and tonic type seizures at later stages. qkI, encoding an RNA binding protein, was identified as a candidate for this mutation. Through the binding to pre-mRNA, QKI may be involved in processing, localization, and protein expression of mRNA for myelin proteins. In addition, we found a novel function of qkI in smooth muscle cell (SMC) differentiation during embryonic blood vessel formation.
A mouse model of Rubinstein-Taybi syndrome (RTS) was generated by an insertional mutation into the cyclic AMP response element-binding protein (CREB) -binding protein (Crebbp) gene. Heterozygous Crebbp-deficient mice, which had truncated CBP protein containing the CREB-binding domain, showed clinical features of RTS, such as growth retardation (100%), retarded osseous maturation (100%), hypoplastic maxilla with narrow palate (100%), cardiac anomalies (15%) and skeletal abnormalities (7%) . Tests for memory storage such as the step-through-type passive avoidance test showed that mice were deficient in long-term memory (LTM) . From this observation, it is expected that drugs that modulate CREB function by enhancing cAMP signaling might yield an effective treatment for the memory defect (s) of Crebbp+/- mice. Actually Bourtchouladze et al. designed a cell-based drug screen and discovered inhibitors of phosphodiesterase 4 (PDE4) to be particularly effective enhancers of CREB function. They demonstrated that the inhibitor abolished the long-term memory defect of Crebbp+/- mice, suggesting that PDE4 inhibitors may be used to treat the cognitive dysfunction of RTS patients. Taken together, these results indicate that mouse models for human diseases are useful for functional genomic, medical genomics and pharmacogenomics.

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