• Feedback Between Clock Genes and Neuropeptides: One major discovery revealed that molecular and neuronal rhythms are tightly intertwined. Using ex vivo cultured fly brains with live fluorescent reporters, the lab demonstrated a feedback loop between the core clock protein CLK and the neuropeptide PDF, which is secreted by s-LNv pacemaker neurons:
  - When CLK levels are high, pdf gene expression is suppressed, likely through intermediate transcription factors like DHR38.
  - Conversely, PDF signaling back to clock neurons is essential to maintain rhythmic CLK-driven transcription.
  This reciprocal CLK–PDF loop was the first evidence that intercellular communication directly regulates core clock machinery — showing that the circadian system is not merely a collection of autonomous clocks, but a synchronized network of “talking” neurons.

• Networks Buffer Weak Clocks: Surprisingly, even when molecular clock oscillations are drastically weakened (by ~90% reduction in gene expression), flies can still maintain rhythmic behavior — but only if PDF signaling is intact. Without PDF, behavior becomes arrhythmic. This shows that PDF neurons can compensate for weak cellular clocks by stabilizing rhythms at the network level. It’s a compelling example of how intercellular signaling helps preserve behavior in the face of cellular noise or damage.

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• Linking the Clock to Metabolism: The Kadener Lab also studies how circadian rhythms connect with other physiological systems, like metabolism. In collaboration with metabolic biologists, they identified Cabut (CBT) as a transcription factor that links sugar consumption to the clock:
  - The Mondo-Mlx nutrient-sensing pathway induces cbt after sugar intake.
  - CBT represses metabolic genes and modulates circadian gene expression.F
  - Flies lacking CBT show both metabolic defects and altered circadian behavior.
  This work (Bartok et al., EMBO J. 2015) revealed a mechanism through which feeding can gate the clock, aligning nutrient signals with daily physiological cycles. It exemplifies the lab’s broader mission to understand how external cues and internal states converge on circadian regulation.