Protein synthesis is critical for circadian clock function, but little is known of how translational regulationcontrols the master pacemaker in mammals, the suprachiasmatic nucleus (SCN). Here we demonstrate that the pivotal translational repressor, the eukaryotic translational initiation factor 4E binding protein 1 (4E-BP1), is rhythmically regulated via the mechanistic target of rapamycin (mTOR) signaling in the SCN and preferentially represses vasoactive intestinal peptide (Vip) mRNA translation. Knockout (KO) of Eif4ebp1 (gene encoding 4E-BP1) leads to upregulation of VIP and higher amplitude of molecular rhythms in the SCN. Consequently, the 4E-BP1 null mice exhibit accelerated re-entrainment to a shifted light/dark cycle and are more resistant to the rhythm-disruptive effects of constant light. Conversely, in Mtor+/- mice VIP expression is decreased and susceptibility to the effects of constant light is increased. These results reveal a key role for mTOR/4E-BP1-mediated translational control in regulating entrainment and synchrony of the master clock.
Bibliographical noteFunding Information:
We thank Michael Rosbash, Isaac Edery, Erik Herzog, and Jane Stewart for advice and critical reading of the manuscript and Maritza Jaramillo, Alex Gavrila, Annie Sylvestre, and Isabelle Harvey for excellent technical assistance. We are indebted to Joseph Takahashi for his generous gift of the mPER2::LUC transgenic mice, Sara C. Kozma for the mtor floxed mice, and Linda Penn and Manfred Schwab for the SHEP neuroblastoma cell line. This work was supported by Canadian Institute of Health Research (CIHR) Grants MOP 114994 to N.S. and MOP 13625 to S.A. and by National Science Foundation (NSF) Grant IOS-0920417 to A.C.L.. N.S. is a senior international research scholar of the Howard Hughes Medical Institute (HHMI). R.C. is a Fonds de recherche du Québec – Santé (FRQS) Postdoctoral Training Award recipient.