Molecular Mechanism of Circadian Signal Generation in Mammals

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1. Involvement of protein-tyrosine kinase (PTK) in generation of the circaadian rhythm. We found that continuous infusion of insulin into rat brain eliminated the circadian rhythms completely. From this finding, we examined the problem of whether PTK was really involved in the circadian signal generation. During the course of this investigation, we isolated a new type of PTK from neonatal rat brain and named it CSK. We showed that this enzyme specifically phosphorylates the C-terminal tyrosine residues of src-family PTKs and that it inhibited the latter activities. We obtained several lines of evidence that CSK might play critical roles in neuronal differentiation, immumne regulation and carcinogenesis. We showed that PTK activity of p60^<c-src> in the suprachiasmatic nucleus (SCN) exhibited the daily change, but we have not obtained evidence yet that CSK is specifically involved in this mechanism. 2. Relationship between rhythm generation and cell cycle. We isolated a D type G1 cyclin, a regulatory protein for cell cycle, from matured brain, in which neurons lose their proliferating abilities. We are now examining how cell cycle regulation and circadian signal generation are interconnected. 3. Central regulation of energy metabolism. It is known that the SCN is roughly divided into two parts, the dorsomedial and ventrolateral parts, and that the cicadian clock is located in the former and the retinohypothalamic tract which is involved in synchronization of the circadian period to an environmental LD cycle is projected to the latter. We found that the regulatory center for energy supply to the brain is located in the latter and obtained evidence suggesting that these functions are cooperatively regulated with the circadian signal generation.