bims-ciryme 2019-06-09 papers

Issue of 2019‒06‒09
two papers selected by
Gabriela Da Silva Xavier
University of Birmingham

Trends Endocrinol Metab. 2019 May 30. pii: S1043-2760(19)30086-4. [Epub ahead of print]

Circadian Clocks and Cancer: Timekeeping Governs Cellular Metabolism.

The circadian clock is a biological mechanism that dictates an array of rhythmic physiological processes. Virtually all cells contain a functional clock whose disruption results in altered timekeeping and detrimental systemic effects, including cancer. Recent advances have connected genetic disruption of the clock with multiple transcriptional and signaling networks controlling tumor initiation and progression. An additional feature of this circadian control relies on cellular metabolism, both within the tumor microenvironment and the organism systemically. A discussion of major advances related to cancer metabolism and the circadian clock will be outlined, including new efforts related to metabolic flux of transformed cells, metabolic heterogeneity of tumors, and the implications of circadian control of these pathways.

Keywords: circadian clock cancer; epigenetics; metabolism; oncogenes; tumor suppressors

DOI: https://doi.org/10.1016/j.tem.2019.05.001

Elife. 2019 Jun 04. pii: e44927. [Epub ahead of print]8

Dissociating orexin-dependent and -independent functions of orexin neurons using novel Orexin-Flp knock-in mice.

Srikanta Chowdhury, Chi Jung Hung, Shuntaro Izawa, Ayumu Inutsuka, Meiko Kawamura, Takashi Kawashima, Haruhiko Bito, Itaru Imayoshi, Manabu Abe, Kenji Sakimura, Akihiro Yamanaka.

Uninterrupted arousal is important for survival during threatening situations. Activation of orexin/hypocretin neurons is implicated in sustained arousal. However, orexin neurons produce and release orexin as well as several co-transmitters including dynorphin and glutamate. To disambiguate orexin-dependent and -independent physiological functions of orexin neurons, we generated a novel Orexin-flippase (Flp) knock-in mouse line. Crossing with Flp-reporter or Cre-expressing mice showed gene expression exclusively in orexin neurons. Histological studies confirmed that orexin was knock-out in homozygous mice. Orexin neurons without orexin showed altered electrophysiological properties, as well as received decreased glutamatergic inputs. Selective chemogenetic activation revealed that both orexin and co-transmitters functioned to increase wakefulness, however, orexin was indispensable to promote sustained arousal. Surprisingly, such activation increased the total time spent in cataplexy. Taken together, orexin is essential to maintain basic membrane properties and input-output computation of orexin neurons, as well as to exert awake-sustaining aptitude of orexin neurons.

Keywords: cataplexy; chemogenetics; electrophysiology; flippase recombinase; mouse; neuroscience; orexin/hypocretin; sleep/wakefulness

DOI: https://doi.org/10.7554/eLife.44927