BibTex format
@article{Maywood:2018:10.1073/pnas.1811438115,
author = {Maywood, ES and Elliott, TS and Patton, AP and Krogager, TP and Chesham, JE and Ernst, RJ and Beranek, V and Brancaccio, M and Chin, JW and Hastings, MH},
doi = {10.1073/pnas.1811438115},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
pages = {E12388--E12397},
title = {Translational switching of Cry1 protein expression confers reversible control of circadian behavior in arrhythmic Cry-deficient mice},
url = {http://dx.doi.org/10.1073/pnas.1811438115},
volume = {115},
year = {2018}
}
RIS format (EndNote, RefMan)
TY - JOUR
AB - The suprachiasmatic nucleus (SCN) is the principal circadian clock of mammals, coordinating daily rhythms of physiology and behavior. Circadian timing pivots around self-sustaining transcriptional–translational negative feedback loops (TTFLs), whereby CLOCK and BMAL1 drive the expression of the negative regulators Period and Cryptochrome (Cry). Global deletion of Cry1 and Cry2 disables the TTFL, resulting in arrhythmicity in downstream behaviors. We used this highly tractable biology to further develop genetic code expansion (GCE) as a translational switch to achieve reversible control of a biologically relevant protein, Cry1, in the SCN. This employed an orthogonal aminoacyl-tRNA synthetase/tRNACUA pair delivered to the SCN by adeno-associated virus (AAV) vectors, allowing incorporation of a noncanonical amino acid (ncAA) into AAV-encoded Cry1 protein carrying an ectopic amber stop codon. Thus, translational readthrough and Cry1 expression were conditional on the supply of ncAA via culture medium or drinking water and were restricted to neurons by synapsin-dependent expression of aminoacyl tRNA-synthetase. Activation of Cry1 translation by ncAA in neurons of arrhythmic Cry-null SCN slices immediately and dose-dependently initiated TTFL circadian rhythms, which dissipated rapidly after ncAA withdrawal. Moreover, genetic activation of the TTFL in SCN neurons rapidly and reversibly initiated circadian behavior in otherwise arrhythmic Cry-null mice, with rhythm amplitude being determined by the number of transduced SCN neurons. Thus, Cry1 does not specify the development of circadian circuitry and competence but is essential for its labile and rapidly reversible activation. This demonstrates reversible control of mammalian behavior using GCE-based translational switching, a method of potentially broad neurobiological interest.
AU - Maywood,ES
AU - Elliott,TS
AU - Patton,AP
AU - Krogager,TP
AU - Chesham,JE
AU - Ernst,RJ
AU - Beranek,V
AU - Brancaccio,M
AU - Chin,JW
AU - Hastings,MH
DO - 10.1073/pnas.1811438115
EP - 12397
PY - 2018///
SN - 0027-8424
SP - 12388
TI - Translational switching of Cry1 protein expression confers reversible control of circadian behavior in arrhythmic Cry-deficient mice
T2 - Proceedings of the National Academy of Sciences of the United States of America
UR - http://dx.doi.org/10.1073/pnas.1811438115
UR - http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000454302600033&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
UR - http://hdl.handle.net/10044/1/78907
VL - 115
ER -