A fully functional central and peripheral circadian clock is not essential for reproduction and development to term, but has critical roles peri-natally and post-partum.

INTRODUCTIONThe past decade has witnessed spectacular advances in our understanding of the genetic basis of circadian timing in mammals. The circadian pacemakers within the suprachiasmatic nucleus (SCN) of the hypothalamus provide a crucial function in conducting a circadian repertoire throughout the body, acting on peripheral oscillators in all major body organs and tissues, with profound effects on general systemic physiology (Reppert and Weaver 2002;Hastings et al. 2003;Lowrey and Takahashi 2004;Saper et al. 2005). In both brain and periphery, the molecular clockwork operates as a series of interlocked autoregulatory feedback loops in which CLOCK:BMAL1 heterodimers bind to E-box DNA sequences contained within genes encoding transcriptional repressors PER and CRY. Following their accumulation in the cytoplasm, PER:CRY complexes translocate to the nucleus after a delay of several hours and repress the activity of constitutively bound CLOCK:BMAL1 complexes. These inhibitory complexes are then degraded following a further delay, and the consequent derepression of CLOCK:BMAL1 activity initiates the next circadian cycle of Per and Cry transcription.We have now come to recognize the all-pervasive nature of circadian timing in biology, and the next challenge is to unravel the mechanisms and pathways involved in mediating the effects of the clocks on physiology and metabolism. The general prevalence of many diseases is also marked by a strong circadian component in morbidity, and circadian mutants are often characterized by unexpected side effects in a wide range of pathologies, including malignancy and metabolic and cardiovascular defects. Mutations in various elements of this core molecular clock have been described, many of which result in either arrhythmia or alteration in period of rest/activity and sleep cycles. Genetically mediated desynchronization of central pacemaker function is also strongly implicated as the primary causal mechanism of familial advanced sleep phase syndrome (FASPS), and unraveling the complexities of how circadian mutations act on both central and peripheral pacemakers will reveal important new insight into both the normal regulation of sleep and the pathologies associated with sleep disruption.As in many areas of biology, much of our recent understanding has come from the use of genetically modified mice, allowing studies of incredible sophistication in a species that has an "amenable" genome. Many of the chapters in this volume are devoted to a detailed exposition of the molecular regulation of circadian timing and the impact of clocks on both normal physiology and disease processes. Here, we describe the biology of the first bona fide circadian mutation ever discovered in a mammal, the tau mutation of the Syrian hamster. We explore the impact that this timing mutation has on both the daily and seasonal biology of this species and then describe the same mutation in genetically modified mice. Here, we are able to use the power of mouse genetics to demonstrate some unexpected features of t...

INTRODUCTIONThe previous decade has witnessed major, indeed astonishing, advances in our understanding of the molecular genetic and cellular bases to circadian timing in mammals (Reppert and Weaver 2002;Lowrey and Takahashi 2004). The SCN of the hypothalamus were first revealed as the "body clock" more than 30 years ago (Weaver 1998). They remain preeminent as the pacemaker responsible for coordinating circadian physiology across the organism and synchronizing it to solar time by retinally mediated entrainment. But in addition to the SCN, we now appreciate that most major organ systems and diverse cell types contain local circadian clockworks and that SCN-dependent synchronization of these local clocks and their dependent transcriptomes orchestrates daily physiology (Akhtar et al. 2002;Panda et al. 2002). The SCN are therefore no longer thought of as coercing a passive periphery into rhythmic behavior; rather, they harness the intrinsic rhythmicity of organs, both sustaining their amplitude and setting their phase. This precise and elaborate temporal coordination of physiology underlies the marked daily prevalence of morbidity in cardiovascular, metabolic, and other diseases (Hastings et al. 2003). Moreover, circadian disturbance, be it environmental or genetic, is linked to malignancy and metabolic and mental illness. Understanding how the SCN operate as a pacemaker tissue and how their output coordinates circadian physiology are outstanding questions with considerable relevance to human health. They also provide a cardinal example of how regulated gene expression can control complex behavior-the Holy Grail of molecular neurobiology. The purpose of this chapter is to review recent studies from our laboratories that have addressed these issues. Our broad strategy has been to use real-time imaging of circadian gene expression to explore molecular timekeeping in genetically modified mice. We offer specific examples illustrating how the period of the central and peripheral clocks is determined by the rate of proteasomal degradation of circadian proteins, how neuropeptidergic signaling synchronizes and sustains cellular circadian pacemaking in the SCN, and how behavioral control by the SCN is mediated via neuropeptides not required for pacemaking but necessary for downstream signaling. Finally, we consider how SCN outputs coordinate metabolically relevant pathways, focusing on liver function. It is likely that the relevance of clocks to medicine will expand far beyond sleep disorders to encompass metabolic disturbances of many kinds. Understanding the cellular and molecular genetic bases of peripheral circadian physiology is therefore a strategic aim of the field. SETTING CELLULAR CIRCADIAN PERIOD BY REGULATED PROTEASOMAL DEGRADATIONThe cellular oscillator of the SCN is viewed as a series of interlocked transcriptional/posttranslational feedback loops (Reppert and Weaver 2002;Lowrey and Takahashi 2004). Expression of the genes encoding the negative regulators Cryptochrome (Cry) and Period (Per) is trans-activated at...

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