Mice that are homozygous for the targeted mutation are viable, but experience high postnatal mortality between postnatal week 1 and 2 due to thermoregulatory defect. The Donating Investigator reports that postnatal survival is improved if temperature is kept at 82.5 F. Homozygous males are fertile, homozygous females are subfertile. No gene product (protein) is detected by RIA (radioimmunoassay) analysis of hypothalamus, cerebral cortex, kidney, and stomach tissues in homozygotes. Homozygotes exhibit sustained hyperactivity, shortened circadian period and abnormal circadian phase shifting with 50% reduction in the magnitude of light cued phase shift. Homozygous mice lack the light stimulation increase of sympathetic nerve activity and plasma corticosterone that is observed in wildtype mice. Testicular aging is delayed in 15-month old male homozygotes; reactive oxygen species generation and apoptosis in the testis is reduced. Young male homozygotes (4 month old) exhibit decreased steroidogenesis with lower seminal vesicle weight, low testosterone level, and low expression levels of steroidogenic acute regulatory protein (StAR) and 3β-hydroxysteroid dehydrogenase (3βHSD). After crush injury, homozygotes have impaired peripheral nerve axon regeneration. Homozygotes also have increased sensitivity to experimental autoimmune encephalomyelitis (EAE). This mutant mouse strain may be useful in studies of photo-entrainment of circadian rhythm and other physiological changes induced by light, behavior, autoimmunity and inflammation, and peripheral nerve repair.
