Autonomous clocks: cellular design, mechanism and function
Latest advances in biological timing studies substantiate an emerging concept of autonomous clocks that are normally entrained by the cell cycle and/or the circadian clock to run in synchrony, but have evolved to run independently to regulate different cellular events (Mofatteh et al., 2021 eLife). In this realm, we have pioneered the discovery of an organelle clock. We found that an autonomous clock initiates and times centriole biogenesis (Aydogan et al., 2018 JCB; Aydogan et al., 2020 Cell).
Following up on our initial discovery and to advance this emerging field forward, we pursue three main avenues that promise a deeper understanding of mechanisms that govern biological timing.
Emerging mechanisms and functions of autonomous clocks in organelle biogenesis and cytoskeletal organization:
We investigate previously underappreciated cyclic phenomena to test for autonomous clock mechanisms in organelle biogenesis and cytoskeletal organization. We have been focusing our efforts on the dynamics of mitochondria, endoplasmic reticulum and membrane cleavages of the early Drosophila embryo. To address our questions, we take advantage of advanced microscopy, microinjection-based biochemistry, ex vivo extracts, and mathematical modelling coupled with dosage genetics. In this endeavour, we are always keen to collaborate with other groups to bring in novel experimental designs, most notably including our recent collaborations on laser ablations with Dr. Miquel Rosas Salvans and Prof. Sophie Dumont at UCSF.
Design of biological “phase-lockers”:
If the cell cycle oscillator (CCO) appears to drive a biological event at the same pace as cell divisions, yet the very biological event can sustain its periodicity even in the absence of the cell cycle, this hints at the possibility that the cell cycle oscillator may act as a "phase-locker" (as opposed to a "master clock"). In this model, the CCO could normally entrain a network of local oscillators to run at the same pace, but when the CCO is silenced, each of these local oscillators could act as autonomous clocks to regulate the timely execution of a specific event. Several experimental predictions of the phase-locking model have been proposed (including in our group's recent piece, Mofatteh et al. eLife, 2021), so we are actively pursuing to test these in the laboratory. In this realm, we have been collaborating with Prof. Shelagh Campbell (of U. Alberta) to understand the genetic basis of phase-locking in the context of the cell cycle.
Fitness advantages of autonomous clocks in evolution and development:
Our lab is slowly beginning to investigate how autonomous clocks might have evolved. Strikingly, while in some species/tissues the autonomy is preserved even in wild-type conditions, in others the autonomy appears redundant due to robust phase-locking (as described above). Currently, we focus on how some aspects of cytoplasmic organization, which can occur independently of the nuclear divisions cycles, may confer fitness advantages in evolution and development.