Biology subjects

Alhashem, Z.

Publications and source records attributed to Alhashem, Z..

4 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↗

bioRxiv2022

Trunk neural crest migratory position and asymmetric division predict terminal differentiation

The generation of complex structures during embryogenesis requires the controlled migration and differentiation of cells from distant origins. How migration and differentiation are coordinated and impact each other to form functional structures is not fully understood. Neural crest cells migrate extensively giving rise to many cell types. In the trunk, neural crest migrate collectively forming chains comprised of cells with distinct migratory identities: one leader cell at the front of the group directs migration, while followers track the leader forming the body of the chain. Herein we analysed the relationship between trunk neural crest migratory identity and terminal differentiation. We found that trunk neural crest migration and fate allocation is coherent. Leader cells that initiate movement give rise to the most distal derivativities. Interestingly, the asymmetric division of leaders separates migratory identity and fate. The distal daughter cell retains the leader identity and clonally forms the Sympathetic Ganglia. The proximal sibling migrates as a follower and gives rise to Schwann cells. The sympathetic neuron transcription factor phox2bb is strongly expressed by leaders from early stages of migration, suggesting that specification and migration occur concomitantly and in coordination. Followers divide symmetrically and their fate correlates with their position in the chain.

developmental biology↗

bioRxiv2021

Notch controls the cell cycle to define leader versus follower identities during collective cell migration.

Coordination of cell proliferation and migration is fundamental for life, and its dysregulation has catastrophic consequences, as cancer. How cell cycle progression affects migration, and vice-versa, remains largely unknown. We address these questions by combining in silico modelling and in vivo experimentation in the zebrafish Trunk Neural Crest (TNC). TNC migrate collectively, forming chains with a leader cell directing the movement of trailing followers. We show that the acquisition of migratory identity is autonomously controlled by Notch signalling in TNC. High Notch activity defines leaders, while low Notch determines followers. Moreover, cell cycle progression is required for TNC migration and is regulated by Notch. Cells with low Notch activity stay longer in G1 and become followers, while leaders with high Notch activity quickly undergo G1/S transition and remain in S-phase longer. We propose that migratory behaviours are defined through the interaction of Notch signalling and cell cycle progression.

developmental biology↗