Biology subjects

Aydogan, M. G.

Publications and source records attributed to Aydogan, M. G..

6 recordsLinked to original sources

bioRxiv2026

Self-reinforcing ROS-aneuploidy feedback loop shapes preimplantation development

Aneuploidy and oxidative stress have each been implicated in impaired embryonic development, yet their relationship remains unclear. Here we discover a self-reinforcing ROS-aneuploidy feedback loop with hysteretic properties in preimplantation development. In human blastocysts, oxidative stress associates with aneuploidy at the population level. Paradoxically, euploid and aneuploid embryos can show overlapping oxidative states, and oxidative stress is uncoupled from morphological, temporal, and maternal age-associated indicators of developmental competence. To test whether oxidative stress and aneuploidy merely co-occur or actively influence one another, we used IVF-derived mouse embryos. Induced chromosome missegregation elevates oxidative damage, while oxidative perturbations promote aneuploidy. Crucially, restoring ROS to baseline levels fails to rescue chromosome integrity or developmental potential, revealing hysteresis whereby outcomes depend more on prior chromosomal history than on instantaneous redox state. Together, these reveal that transient redox perturbations can induce persistent chromosomal alterations that shape developmental outcomes even after redox balance is restored, thereby challenging proposals of ROS as a biomarker of embryonic competence.

developmental biology↗

bioRxiv2024

A mitochondrial redox switch licenses the onset of morphogenesis in animals

Embryos undergo pre-gastrulation cleavage cycles to generate a critical cell mass before transitioning to morphogenesis. The molecular underpinnings of this transition have traditionally centered on zygotic chromatin remodeling and genome activation1,2, as their repression can prevent downstream processes of differentiation and organogenesis. Despite precedents that oxygen depletion can similarly suspend development in early embryos3-6, hinting at a pivotal role for oxygen metabolism in this transition, whether there is a bona fide chemical switch that licenses the onset of morphogenesis remains unknown. Here we discover that a mitochondrial oxidant acts as a metabolic switch to license the onset of animal morphogenesis. Concomitant with the instatement of mitochondrial membrane potential, we found a burst-like accumulation of mitochondrial superoxide (O2-) during fly blastoderm formation. In vivo chemistry experiments revealed that an electron leak from site IIIQo at ETC Complex III is responsible for O2- production. Importantly, depleting mitochondrial O2- fully mimics anoxic conditions and, like anoxia, induces suspended animation prior to morphogenesis, but not after. Specifically, H2O2, and not ONOO-, NO, or HO*, can single-handedly account for this mtROS-based response. We demonstrate that depleting mitochondrial O2- similarly prevents the onset of morphogenetic events in vertebrate embryos and ichthyosporea, close relatives of animals. We postulate that such redox-based metabolic licensing of morphogenesis is an ancient trait of holozoans that couples the availability of oxygen to development, conserved from early-diverging animal relatives to vertebrates.

developmental biology↗

bioRxiv2022

Cytoplasmic divisions without nuclei

Cytoplasmic divisions have been commonly considered a sequel to nuclear divisions, even in the absence of DNA replication. Here we found in fruit fly embryos that the cytoplasm can compartmentalize and divide without nuclei. Our targeted screen for potential necessary and sufficient conditions revealed that, although the cytoplasmic compartments are tightly associated with centrosomes, they can form without astral microtubules and divide without centrioles. Although a focal pool of microtubules is necessary for maintaining cytoplasmic compartments, this is not sufficient for their initial formation. Actin filaments are similarly an essential component of cytoplasmic compartments; however, their myosin II-based contractility is unexpectedly dispensable for divisions. We show that the myosin II-based contractility is instead involved in regulating the pace of these divisions. Importantly, our results revealed that the cytoplasmic divisions without nuclei can occur in a periodic manner autonomously of the Cdk-Cyclin oscillator that normally drives the cell cycle. We demonstrate that such autonomy of cytoplasmic divisions is preserved even in normal development, where it is leveraged to extrude mitotically delayed nuclei from the blastoderm, protecting the synchrony of rapid nuclear divisions against local delays in mitotic entry. We propose that an active coordination between otherwise autonomous cycles of cytoplasmic and nuclear divisions acts as a quality control mechanism for genome integrity and partitioning in development.

cell biology↗

bioRxiv2021

Centriole distal-end proteins CP110 and Cep97 influence cartwheel growth at the proximal-end of centrioles

Centrioles are composed of a central cartwheel tethered to nine-fold symmetric microtubule (MT) blades. The centriole cartwheel and MTs are thought to grow from opposite ends of these organelles, so it is unclear how they coordinate their assembly. We previously showed that an oscillation of Polo-like kinase 4 (Plk4) helps to initiate and time the growth of the cartwheel at the proximal end. Here, we show that CP110 and Cep97 form a complex close to the distal-end of the centriole MTs whose levels rise and fall as the new centriole MTs grow, entrained by the core Cdk/Cyclin oscillator that drives the nuclear divisions in these embryos. These CP110/Cep97 dynamics, however, do not appear to time the period of centriole MT growth directly. Instead, we find that changing the levels of CP110/Cep97 alters the Plk4 oscillation and the growth of the cartwheel at the proximal end. These findings reveal an unexpected crosstalk between factors normally concentrated at opposite ends of the growing centrioles, which may help to coordinate centriole growth.

cell biology↗

bioRxiv2019

A free-running oscillator times and executes centriole biogenesis

The accurate timing of organelle biogenesis and the precise regulation of organelle size are crucial for cell physiology. Centriole biogenesis initiates exclusively in S-phase, when a daughter centriole emerges from the side of a pre-existing mother and grows until it reaches its mothers size. This process is regulated by Polo-like kinase 4 (Plk4), which is recruited to centrioles in oscillatory waves in flies and human cells 1,2. The nature and function of Plk4 oscillations is, however, unknown. Here we discover that Plk4 forms an adaptive oscillator at the base of the growing centriole, whose function is to time and set the duration of centriole biogenesis in Drosophila embryos. We demonstrate that the Plk4 oscillator is free-running of, but is entrained and calibrated by, the core Cdk/Cyclin cell-cycle oscillator, explaining how centrioles can duplicate independently of the cell cycle 3-5. Mathematical modelling and further experiments indicate that the Plk4 oscillator is generated by a time-delayed negative-feedback loop in which Plk4 recruitment to, and dissociation from, the centriole is monitored via changes in the affinity-state of its centriolar receptor, Asterless. We postulate that such organelle-specific autonomous oscillators could regulate the timing and execution of organelle biogenesis more generally.

cell biology↗

bioRxiv2018

A positive feedback loop drives centrosome maturation in flies

Centrosomes are formed when mother centrioles recruit pericentriolar material (PCM) around themselves. The PCM expands dramatically as cells prepare to enter mitosis (a process termed centrosome maturation), but it is unclear how this expansion is achieved. In flies, Spd-2 and Cnn form an extensive scaffold around the mother centriole that recruits other components of the mitotic PCM, and the Polo-dependent phosphorylation of Cnn at the centrosome is crucial for scaffold assembly. Here we show that, like Cnn, Spd-2 is specifically phosphorylated at centrosomes. This phosphorylation appears to create multiple phosphorylated S-S/T(p) motifs that allow Spd-2 to recruit Polo to the expanding scaffold. If Spd-2 cannot recruit Polo to the expanding scaffold, the scaffold is initially assembled around the mother centriole, but it cannot expand outwards, and centrosome maturation fails. We conclude that Spd-2, Polo and Cnn cooperate to form a positive feedback loop that drives the dramatic expansion of the mitotic centrosome in flies.

cell biology↗