The negative limb is composed of the period and timeless proteins, PER and TIM, respectively. They dimerize and cyclically inhibit their own transcription via inactivation of the CLK/CYC complex selleck chemicals (see Nitabach and Taghert, 2008 for a review). This core

circadian clock also governs the rhythmic expression and/or activity of many other genes, which ultimately result in behavioral, biochemical, and physiological rhythms. A very similar model, with many orthologous genes and proteins, describes the mammalian core clock. The Drosophila clock functions within many cells and tissues. There are approximately 75 circadian neurons per hemisphere in the adult CNS, including nine to ten pairs of ventral lateral neurons (LNvs). They express clock proteins as well as the neuropeptide pigment-dispersing factor (PDF). The four pairs of small ventral

lateral neurons (s-LNvs) are important for maintaining clock neuron synchrony and for behavioral rhythms in constant darkness as well as morning Anticancer Compound Library locomotor activity ( Lin et al., 2004 and Yoshii et al., 2009). These neurons have long axonal projections, which were reported to undergo daily changes in morphology ( Fernández et al., 2008). These rhythmic changes are also activity dependent ( Depetris-Chauvin et al., 2011) and may be related to activity-dependent neuronal changes extensively investigated in vertebrate as well as invertebrate model systems ( Bushey and Cirelli, 2011, Greer and Greenberg, 2008, Tavosanis, 2012 and West and Greenberg, 2011). There are several other well-studied examples of clock-controlled changes in neuronal morphology. Vertebrate photoreceptor cells are a classic example (Behrens and Wagner, 1996 and La Vail, 1976), and insect axons within the lamina of the optic lobe also undergo a circadian shrinking and swelling cycle (Pyza and

Meinertzhagen, 1995 and Weber et al., 2009). In zebrafish, the clock rather than the sleep/wake cycle has a primary role in driving changes in synapse number within hypocretin/orexin (HCRT) neurons (Appelbaum et al., 2010). A circadian connection is usually based on one or both of two criteria: (1) the oscillations persist in constant darkness, i.e., a light-dark (LD) cycle is unnecessary; (2) they are abolished in arrhythmic clock gene mutants. However, there is no known of direct molecular link between the core clock and rhythmic remodeling of s-LNv axonal projections (Fernández et al., 2008), nor have they been linked to circadian behavioral rhythms. How then does the core molecular clock direct this rhythmic remodeling and is there an impact on circadian behavior? To elucidate molecular mechanisms, we turned to our previous analysis of mRNAs specifically enriched in the circadian clock neurons of Drosophila melanogaster ( Kula-Eversole et al., 2010 and Nagoshi et al., 2010). Among the top genes enriched in large LNvs as well as in small LNvs is the Drosophila ortholog of Mef2.