TY - JOUR
T1 - BMAL1-Driven Tissue Clocks Respond Independently to Light to Maintain Homeostasis
AU - Welz, Patrick Simon
AU - Zinna, Valentina M.
AU - Symeonidi, Aikaterini
AU - Koronowski, Kevin B.
AU - Kinouchi, Kenichiro
AU - Smith, Jacob G.
AU - Guillén, Inés Marín
AU - Castellanos, Andrés
AU - Crainiciuc, Georgiana
AU - Prats, Neus
AU - Caballero, Juan Martín
AU - Hidalgo, Andrés
AU - Sassone-Corsi, Paolo
AU - Benitah, Salvador Aznar
N1 - Funding Information:
We thank Manolis Pasparakis for kindly providing us with the liver-specific Alfp-Cre mouse line. Research in the lab of S.A.B. is supported by the European Research Council (ERC), the government of Cataluña ( SGR grant), the government of Spain (MINECO), and the Fundación Botín and Banco Santander through Santander Universities. P.-S.W. was supported by an EMBO long-term fellowship and by a Juan de la Cierva fellowship from the Spanish MINECO . V.M.Z. has received financial support through the “la Caixa” INPhINIT Fellowship Grant for Doctoral Studies at Spanish Research Centers of Excellence, “la Caixa” Foundation , Barcelona (ID 100010434). The fellowship code is LCF/BQ/IN17/11620018 . The project has received funding from the European Union ’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement no. 713673 . A.S. was supported by a MINECO grant. I.M.G. was supported by a MMRES fellowship from the Barcelona Institute of Science and Technology (BIST). K.K. was supported by a postdoctoral fellowship from the Japan Society for the Promotion of Science (JSPS). K.B.K. was supported by a postdoctoral fellowship from NIH-NINDS , T32 5T32NS045540 . The CNIC is supported by the MINECO and the Pro-CNIC Foundation and is a Severo Ochoa Center of Excellence (MINECO award SEV-2015-0505 ). IRB Barcelona is the recipient of a Severo Ochoa Award of Excellence from MINECO (Government of Spain). We thank Veronica Raker for manuscript editing.
Funding Information:
We thank Manolis Pasparakis for kindly providing us with the liver-specific Alfp-Cre mouse line. Research in the lab of S.A.B. is supported by the European Research Council (ERC), the government of Catalu?a (SGR grant), the government of Spain (MINECO), and the Fundaci?n Bot?n and Banco Santander through Santander Universities. P.-S.W. was supported by an EMBO long-term fellowship and by a Juan de la Cierva fellowship from the Spanish MINECO. V.M.Z. has received financial support through the ?la Caixa? INPhINIT Fellowship Grant for Doctoral Studies at Spanish Research Centers of Excellence, ?la Caixa? Foundation, Barcelona (ID 100010434). The fellowship code is LCF/BQ/IN17/11620018. The project has received funding from the European Union's Horizon 2020 research and innovation program under the Marie Sk?odowska-Curie grant agreement no. 713673. A.S. was supported by a MINECO grant. I.M.G. was supported by a MMRES fellowship from the Barcelona Institute of Science and Technology (BIST). K.K. was supported by a postdoctoral fellowship from the Japan Society for the Promotion of Science (JSPS). K.B.K. was supported by a postdoctoral fellowship from NIH-NINDS, T32 5T32NS045540. The CNIC is supported by the MINECO and the Pro-CNIC Foundation and is a Severo Ochoa Center of Excellence (MINECO award SEV-2015-0505). IRB Barcelona is the recipient of a Severo Ochoa Award of Excellence from MINECO (Government of Spain). We thank Veronica Raker for manuscript editing. P.-S.W. and S.A.B. designed the study. P.-S.W. conceived and generated the Bmal1-stopFL mouse model. P.-S.W. V.M.Z. A.C. I.M.G. K.B.K. K.K. J.G.S. and G.C. performed research. K.B.K. and J.G.S. designed and analyzed all experiments related to the metabolic cages. A.S. performed the statistical analysis of the RNA-sequencing data. N.P. characterized histology samples. J.M.C. supervised the IntelliCage experiment. P.-S.W. and S.A.B. wrote the manuscript with the input of all authors. P.-S.W. A.H. P.S.-C. and S.A.B. supervised and coordinated the project. The authors declare no competing interests.
Funding Information:
We thank Manolis Pasparakis for kindly providing us with the liver-specific Alfp-Cre mouse line. Research in the lab of S.A.B. is supported by the European Research Council (ERC), the government of Cataluña (SGR grant), the government of Spain (MINECO), and the Fundación Botín and Banco Santander through Santander Universities. P.-S.W. was supported by an EMBO long-term fellowship and by a Juan de la Cierva fellowship from the Spanish MINECO. V.M.Z. has received financial support through the “la Caixa” INPhINIT Fellowship Grant for Doctoral Studies at Spanish Research Centers of Excellence, “la Caixa” Foundation, Barcelona (ID 100010434). The fellowship code is LCF/BQ/IN17/11620018. The project has received funding from the European Union's Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement no. 713673. A.S. was supported by a MINECO grant. I.M.G. was supported by a MMRES fellowship from the Barcelona Institute of Science and Technology (BIST). K.K. was supported by a postdoctoral fellowship from the Japan Society for the Promotion of Science (JSPS). K.B.K. was supported by a postdoctoral fellowship from NIH-NINDS, T32 5T32NS045540. The CNIC is supported by the MINECO and the Pro-CNIC Foundation and is a Severo Ochoa Center of Excellence (MINECO award SEV-2015-0505). IRB Barcelona is the recipient of a Severo Ochoa Award of Excellence from MINECO (Government of Spain). We thank Veronica Raker for manuscript editing. P.-S.W. and S.A.B. designed the study. P.-S.W. conceived and generated the Bmal1-stopFL mouse model. P.-S.W. V.M.Z. A.C. I.M.G. K.B.K. K.K. J.G.S. and G.C. performed research. K.B.K. and J.G.S. designed and analyzed all experiments related to the metabolic cages. A.S. performed the statistical analysis of the RNA-sequencing data. N.P. characterized histology samples. J.M.C. supervised the IntelliCage experiment. P.-S.W. and S.A.B. wrote the manuscript with the input of all authors. P.-S.W. A.H. P.S.-C. and S.A.B. supervised and coordinated the project. The authors declare no competing interests.
PY - 2019/5/30
Y1 - 2019/5/30
N2 - Circadian rhythms control organismal physiology throughout the day. At the cellular level, clock regulation is established by a self-sustained Bmal1-dependent transcriptional oscillator network. However, it is still unclear how different tissues achieve a synchronized rhythmic physiology. That is, do they respond independently to environmental signals, or require interactions with each other to do so? We show that unexpectedly, light synchronizes the Bmal1-dependent circadian machinery in single tissues in the absence of Bmal1 in all other tissues. Strikingly, light-driven tissue autonomous clocks occur without rhythmic feeding behavior and are lost in constant darkness. Importantly, tissue-autonomous Bmal1 partially sustains homeostasis in otherwise arrhythmic and prematurely aging animals. Our results therefore support a two-branched model for the daily synchronization of tissues: an autonomous response branch, whereby light entrains circadian clocks without any commitment of other Bmal1-dependent clocks, and a memory branch using other Bmal1-dependent clocks to “remember” time in the absence of external cues. Light can synchronize circadian clocks within the epidermis in the absence of BMAL1-driven clocks in all other tissues.
AB - Circadian rhythms control organismal physiology throughout the day. At the cellular level, clock regulation is established by a self-sustained Bmal1-dependent transcriptional oscillator network. However, it is still unclear how different tissues achieve a synchronized rhythmic physiology. That is, do they respond independently to environmental signals, or require interactions with each other to do so? We show that unexpectedly, light synchronizes the Bmal1-dependent circadian machinery in single tissues in the absence of Bmal1 in all other tissues. Strikingly, light-driven tissue autonomous clocks occur without rhythmic feeding behavior and are lost in constant darkness. Importantly, tissue-autonomous Bmal1 partially sustains homeostasis in otherwise arrhythmic and prematurely aging animals. Our results therefore support a two-branched model for the daily synchronization of tissues: an autonomous response branch, whereby light entrains circadian clocks without any commitment of other Bmal1-dependent clocks, and a memory branch using other Bmal1-dependent clocks to “remember” time in the absence of external cues. Light can synchronize circadian clocks within the epidermis in the absence of BMAL1-driven clocks in all other tissues.
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U2 - 10.1016/j.cell.2019.05.009
DO - 10.1016/j.cell.2019.05.009
M3 - Article
C2 - 31150620
AN - SCOPUS:85065772479
VL - 177
SP - 1436-1447.e12
JO - Cell
JF - Cell
SN - 0092-8674
IS - 6
ER -