Figure 2.

Daily and annual timing share neurobiological and molecular pathways. In birds and mammals, the annual timing mechanism uses input from the circadian (daily) timing mechanism at the neurobiological and at the molecular level. In birds (a), light regulates the circadian system through photoreceptors in the pineal gland and various opsin-expressing brain areas, with the eyes playing a species-specific role in circadian organization. The avian pineal gland produces melatonin and contains a self-sustained circadian oscillator which, together with the suprachiasmatic nucleus (SCN), regulates daily timing in physiology and behaviour. In mammals (b), light input from the retina stimulates the SCN, which regulates daily timing in behaviour, physiology and melatonin production in the pineal gland. Melatonin receptors in the pars tuberalis (PT) of the pituitary regulate annual timing by thyroid-stimulating hormone (TSH) signalling to the tanycytes in the third ventricle (3V) wall, which in turn regulate thyroid hormone and gonadotropin-releasing hormone signalling, regulating gonadotropin secretion by the PT and subsequent annual timing of reproduction. Contrastingly, in birds (a), melanopsin-positive cerebrospinal fluid-contacting neurons in the 3V wall can directly signal photoperiodic information to the PT-tanycyte pathway, regulating annual timing of reproduction. At the molecular level, the core vertebrate circadian oscillator (c) consists of the BMAL1::CLOCK transcription factor inducing Per and Cry genes which, after dimerization, repress their own promotor activation by the BMAL1::CLOCK dimer. This oscillatory feedback mechanism causes rhythmical induction of BMAL1 which, after dimerizing with CLOCK, produces circadian regulation of output genes like Tef, Hlf and other clock-controlled genes regulating daily rhythms in cellular physiology and metabolism. Synaptic light input signalling to the SCN causes Per induction ((c) lightning symbol) and entrainment to the external light–dark cycle. In mammals, a similar circadian feedback network resides in the PT (d), but here melatonin induces Cry ((d) top lightning symbol), while BMAL1::CLOCK induces Tef and Hlf enhances BMAL1::CLOCK induction of Eya3. Under long winter nights, the induction of Eya3 is fully blocked by melatonin still present in the morning. When morning melatonin is absent during long summer days, EYA3 will cause TSH release, leading to tanycyte thyroid hormone production and, in long-day breeders ((d) bottom lightning symbol), to subsequent gonadotropin production by the pituitary, leading to seasonal gonadal development. ccg, clock-controlled gene. See www.genecards.org for full names of abbreviated genes. (Online version in colour.)