Under conditions of

Under conditions of Selleckchem BAY 73-4506 “forced clock desynchrony” such as a 22 hr LD cycle or constant light, the rhythms from the core and

the shell can become out of phase and animals show split behavioral rhythms or become arrhythmic ( de la Iglesia et al., 2004 and Ohta et al., 2005). Similar to the role in entrainment, enhanced VIPergic synaptic transmission from the core to the shell would make the SCN ensemble more strongly coupled and thus more resistant to the desynchronizing effects of these conditions, whereas decreased VIP level would make the clock more susceptible to the clock-disruptive effects. This model is consistent with the opposite changes of susceptibility to constant light in Eif4ebp1 KO and Mtor+/−mice. In addition to VIP, we examined other mediators of SCN synchrony such as GRP and GABA that may underlie the phenotypes of 4E-BP1 mutants. The expression of the relevant proteins is not altered in the 4E-BP1 KO mice, thus not supporting a role for these mediators in regulation of the clock by 4E-BP1. A previous study showed that mTOR signaling modulates photic entrainment of the SCN clock by facilitating PER1 and PER2 expression selleck inhibitor (Cao et al., 2010). Although 4E-BP1 is a downstream effector of mTOR, pharmacological disruption (i.e., using rapamycin) of mTOR signaling in vivo only transiently inhibits 4E-BP1 activity (up to a couple of hours, unpublished

data) and thus cannot be used to study circadian functions of 4E-BP1. Here we show that 4E-BP1 does not regulate PER1 and

PER2 expression. Thus, the effects of mTOR on PER expression are mediated through other mTOR downstream targets. Besides its role in Vip regulation, 4E-BP1 may have other functions in circadian clocks. 4E-BP1 inhibits translational initiation by binding to eIF4E and impairing the formation of the translational preinitiation complex, which consists of eIF4E, eIF4A, and eIF4G. Indeed, several Astemizole studies have reported the roles of the eIF4E and its binding proteins in circadian clock physiology. For example, knockdown of the eIF4G homolog, NAT1, significantly reduces PER expression and lengthens the behavioral period in Drosophila ( Bradley et al., 2012). Moreover, a recent study reported that the clock coordinates ribosomal biogenesis in the liver by rhythmic activation of the mTOR/4E-BP1/eIF4E pathway ( Jouffe et al., 2013). Therefore, circadian rhythmicity of the mTOR/4E-BP1 signaling may be a general feature of circadian oscillators. Regulation of Vip mRNA translation is a SCN (or VIP-producing tissue)-specific function of the mTOR/4E-BP1 signaling. In the peripheral oscillators, where there is no obvious role for VIP or circadian coupling, the mTOR/4E-BP1 pathway may serve as an output signaling of the circadian clock to coordinate rhythmic mRNA translation. Eif4ebp1 KO mice ( Tsukiyama-Kohara et al.

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