Biology subjects

Hamidzadeh, A.

Publications and source records attributed to Hamidzadeh, A..

5 recordsLinked to original sources

bioRxiv2026

A dynein-driven nucleokinesis program enables neural crest migration through confined tissues in vivo

Cell migration through confined tissue environments requires precise coordination between the nucleus and the cytoskeleton. Translocation of the nucleus through small pores is a limiting step in confined cell migration. Work in immune and cancer cells has illuminated a key role for actin polymerization and Myosin-II contractility in facilitating nucleus translocation through confinement. However, the microtubule cytoskeleton can also adaptively stabilise under confinement. Microtubule-dependent nucleokinesis constitutes an evolutionarily conserved cellular program ensuring directional nucleus translocation by deployment of cytoplasmic dynein motors. However, whether microtubule-driven nucleokinesis can operate during cell migration through confinement remained so far unexplored. The zebrafish neural crest (NC) provides a unique in vivo system to address this question. NC cells are a highly migratory, multipotent precursors of the vertebrate peripheral nervous system, which traverse diverse environments along the anterior-posterior axis of the embryo. In the head, cranial neural crest (cNC) cells migrate through loosely organised tissues, whereas trunk neural crest (tNC) cells navigate narrowly confined tissue spaces. Here, we show that tNC cells engage a microtubule motor-driven program of nuclear deformation and translocation during confined migration in vivo. Under confinement, tNC cells reorganize their microtubules from a perinuclear meshwork into a polarized, centrosome-associated bundle positioned ahead of the nucleus. Laser ablation reveals that this microtubule array actively pulls and deforms the nucleus. Using pharmacological and genetic approaches, we discover that dynein-dependent pulling forces enable nucleus translocation through confinement. Strikingly, this process occurs independently of Rho/ROCK/myosin II-mediated contractility, revealing a novel neuronal-like mode of nucleokinesis operating in confined tissue environments. Together, our findings uncover a conserved nuclear translocation program deployed during neural crest migration and suggest that microtubule-based nucleokinesis represents a fundamental strategy for navigating tissue confinement in vivo during both central and peripheral nervous system development.

cell biology↗

bioRxiv2025

In vivo nuclear envelope adaptation during cell migration across confining embryonic tissue environments

In physiology and in disease, cells often migrate through narrow spaces, such as leukocytes undergoing diapedesis or cancer cells during dissemination. Cultured cells under physical confinement have been shown to experience mechanical stress due to deformation of the nucleus. Nuclear deformation can lead to loss of nuclear integrity and DNA damage, and it has been proposed to underlie cancer initiation and progression. In vivo, the consequences of physical confinement on physiological, developmental cell migration remain so far unexplored. Here, we use the zebrafish neural crest as an in vivo model to address how multipotent embryonic cells respond to physical confinement during developmental migration. By measuring the extracellular space from head to tail along the embryonic body axis, we found that the level of tissue scale confinement increases along the antero-posterior axis. We found that neural crest experience dramatic nuclear deformation during their migrating between adjacent tissues, which quantitatively scales with tissue confinement. By using complementary genetic and mechanical strategies to ablate the surrounding tissue, we observe a rescue of nuclear deformation in vivo. Surprisingly, we found that while deformation of the NC nucleus causes stretching of the nuclear envelope, it does not cause DNA damage even upon extreme deformations. Instead, cells adapt, by decreasing both their DNA damage and LaminB2 levels upon entering confined spaces. In summary, we establish the neural crest as a physiological framework uncovering a dynamic adaptation to tissue confinement in vivo.

developmental biology↗

bioRxiv2020

A molecular clock controls periodically driven cell migration in confined spaces

Navigation through dense, physically confining extracellular matrix is common in invasive cell spread and tissue re-organization, but is still poorly understood. Here, we show that this migration is mediated by cyclic changes in the activity of a small GTP-ase RhoA, dependent on the oscillatory changes in the activity and abundance of the RhoA Guanine Exchange Factor, GEF-H1, triggered by a persistent increase in the intracellular Ca2+ levels. We show that the molecular clock driving these cyclic changes is mediated by two coupled negative feedback loops, dependent on the microtubule dynamics, with the frequency that can be experimentally modulated based on a predictive mathematical model. We further demonstrate that an increasing frequency of the clock translates into a faster cell migration within physically confining spaces. This work lays the foundation for a better understanding of the molecular mechanisms dynamically driving cell migration in complex environments.

systems biology↗

bioRxiv2019

Signaling Diversity Enabled by Rap1-Regulated Plasma Membrane ERK with Distinct Temporal Dynamics

A variety of different signals induce specific responses through a common, ERK-dependent kinase cascade. It has been suggested that signaling specificity can be achieved through precise temporal regulation of ERK activity. Given the wide distrubtion of ERK susbtrates across different subcellular compartments, it is important to understand how ERK activity is temporally regulated at specific subcellular locations. To address this question, we have expanded the toolbox of FRET-based ERK biosensors by creating a series of improved biosensors targeted to various subcellular regions via sequence specific motifs to measure spatiotemporal changes in ERK enzymatic activity. Using these sensors, we showed that EGF induces sustained ERK activity near the plasma membrane in sharp contrast to the transient activity observed in the cytopolasm and nucleus. Furthermore, EGF-induced plasma membrane ERK activity involves Rap1, a noncanonical activator, and controls cell morphology and EGF-induced membrane protrusion dynamics. Our work strongly supports that spatial and temporal regulation of ERK activity is integrated to control signaling specificity from a single extracellular signal to multiple cellular processes.

cell biology↗

bioRxiv2019

The Evolution of Placental Invasion and Cancer Metastasis are Causally Linked

Among mammals, the extent of placental invasion is correlated with vulnerability to malignancy. Animals with more invasive placentation (e.g. humans) are more vulnerable to malignancy, whereas animals with a non-invasive placenta (e.g. ruminants) are less likely to develop malignant cancer. To explain this correlation, we propose the hypothesis of Evolved Levels of Invasibility (ELI) positing that the permissiveness of stromal tissue to invasion is a unitary character affecting both placental and cancer invasion. We provide evidence for this hypothesis by contrasting invasion of human and bovine cancer and placental cells into a lawn of stromal cells from different species. We find that both bovine endometrial and skin fibroblasts are more resistant to invasion of placental and cancer cells than their human counterparts. Gene expression profiling identified genes with high expression in human but not bovine fibroblasts. Knocking down of a subset of them in human fibroblasts leads to significantly stronger resistance to cancer cell invasion. Comparative analysis of gene expression among mammals suggests that humans evolved higher vulnerability to malignancy than the eutherian ancestor, possibly as a correlate of more invasive placentation, and boroeutherians evolved to decrease stromal invasibility. Identifying the evolutionary determinants of stromal invasibility can provide significant insights to develop rational anti-metastatic therapeutics.

cancer biology↗