TGF-alpha: A New Job for an Old Friend

Transforming growth factor (TGF)-alpha is a regulator of cell proliferation and differentiation and has thus been associated with myriad forms of cancer.¹ A recent study by Kramer et al. (2001) identifies a new role for TGF-alpha, as one of the elusive regulators of circadian rhythms of activity and sleep.² It has long been known that the circadian clock drives daily rhythms of activity and sleep, but precious few clues about these output pathways have emerged.

Figure 1. Coronal section through the hypothalamus of a hamster brain showing the SCN and SPZ. Light is signaled to the SCN clock. TGF-alpha is secreted by the SCN, acts on EGF receptors in the SPZ, and inhibits activity during the day.

Humans and animals have precise and persistent rhythms of many behavioral, physiological, metabolic, cellular, and molecular parameters that, although influenced by the environment, are generated by an internal body clock. This clock runs, even in the absence of external time cues such as light, on a period of approximately 24 hours and thus has been dubbed the “circadian” clock.³ In mammals, the circadian clock has been localized to the hypothalamic suprachiasmatic nucleus (SCN).⁴ Several transplant studies suggest that diffusible factors secreted from the SCN and acting locally are involved in the regulation of activity and sleep rhythms by the clock.^5-8 These enigmatic “activity promoters” and “activity inhibitors” have proven difficult to discover.

TGF-alpha appears to be one of these factors. Kramer et al. demonstrate that TGF-alpha is rhythmically secreted by the SCN clock.² In nocturnal rodents, levels are high during the day and low during the night, a phase suggestive of an activity inhibitor. TGF-alpha acts on epidermal growth factor (EGF) receptors located nearby in the subparaventricular zone (SPZ), the major receiver of projections from the SCN. A model reflecting the influence of TGF-alpha on circadian rhythms is illustrated in figure 1. Light modulates the SCN clock via retinal photoreceptors and the SCN rhythmically secretes TGF-alpha. TGF-alpha then acts on SPZ EGF receptors, thereby suppressing activity.²

References

1. Derynck, R. (1992) Adv. Cancer Res. 58:27.
2. Kramer, A. et al. (2001) Science 294:2511.
3. Menaker, M. (1982) “In search of principles of physiological organization in vertebrate circadian systems.” in Vertebrate Circadian Systems: Structure and Physiology, Aschoff, J. et al., eds., Springer-Verlag, Berlin, pp. 1-12.
4. Klein, D.C. et al. eds. (1991) Suprachiasmatic nucleus: the mind's clock. Oxford University Press, New York.
5. Vogelbaum, M.A. & M. Menaker (1992) J. Neurosci. 12:3619.
6. Ralph, M.R. et al. (1990) Science 247:975.
7. Earnest, D.J. et al. (1999) Science 283:693.
8. LeSauter, J. & R. Silver (1999) J. Neurosci. 19:5574.