Actomyosin Contraction at the Cell Rear Drives Nuclear Translocation in Migrating Cortical Interneurons (original) (raw)
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Dynamic modes of the cortical actomyosin gel during cell locomotion and division
Trends in cell biology, 2006
Tight regulation of the contractility of the actomyosin cortex is essential for proper cell locomotion and division. Enhanced contractility leads, for example, to aberrations in the positioning of the mitotic spindle or to anomalous migration modes that allow tumor cells to escape anti-dissemination treatments. Spherical membrane protrusions called blebs occasionally appear during cell migration, cell division or apoptosis. We have shown that the cortex ruptures at sites where actomyosin cortical contractility is increased, leading to the formation of blebs. Here, we propose that bleb formation, which releases cortical tension, can be used as a reporter of cortical contractility. We go on to analyze the implications of spontaneous cortical contractile behaviors on cell locomotion and division and we particularly emphasize that variations in actomyosin contractility can account for a variety of migration modes.
F1000 - Post-publication peer review of the biomedical literature, 2005
During rodent cortex development, cells born in the medial ganglionic eminence (MGE) of the basal telencephalon reach the embryonic cortex by tangential migration and differentiate as interneurons. Migrating MGE cells exhibit a saltatory progression of the nucleus and continuously extend and retract branches in their neuritic arbor. We have analyzed the migration cycle of these neurons using in vitro models. We show that the nucleokinesis in MGE cells comprises two phases. First, cytoplasmic organelles migrate forward, and second, the nucleus translocates toward these organelles. During the first phase, a large swelling that contains the centrosome and the Golgi apparatus separates from the perinuclear compartment and moves rostrally into the leading neurite, up to 30 m from the waiting nucleus. This long-distance migration is associated with a splitting of the centrioles that line up along a linear Golgi apparatus. It is followed by the second, dynamic phase of nuclear translocation toward the displaced centrosome and Golgi apparatus. The forward movement of the nucleus is blocked by blebbistatin, a specific inhibitor of nonmuscle myosin II. Because myosin II accumulates at the rear of migrating MGE cells, actomyosin contraction likely plays a prominent role to drive forward translocations of the nucleus toward the centrosome. During this phase of nuclear translocation, the leading growth cone either stops migrating or divides, showing a tight correlation between leading edge movements and nuclear movements.
Elongator controls cortical interneuron migration by regulating actomyosin dynamics
Cell Research, 2016
The migration of cortical interneurons is a fundamental process for the establishment of cortical connectivity and its impairment underlies several neurological disorders. During development, these neurons are born in the ganglionic eminences and they migrate tangentially to populate the cortical layers. This process relies on various morphological changes that are driven by dynamic cytoskeleton remodelings. By coupling time lapse imaging with molecular analyses, we show that the Elongator complex controls cortical interneuron migration in mouse embryos by regulating nucleokinesis and branching dynamics. At the molecular level, Elongator fine-tunes actomyosin forces by regulating the distribution and turnover of actin microfilaments during cell migration. Thus, we demonstrate that Elongator cell-autonomously promotes cortical interneuron migration by controlling actin cytoskeletal dynamics.
2004
Cortical interneurons originate from the ganglionic eminences and reach their final position in the cortex via tangential migratory routes. The mechanisms of this migration are poorly understood. Here we have performed confocal time-lapse analysis of cell movement in the intermediate zone of embryonic mouse cortical slices in order to directly visualize their mode of migration. Tangentially migrating neurons moved by nucleokinesis, characterized by active phases of discontinuous advances of the nucleus followed by periods of quies-cence. Dissociated cells from the ganglionic eminences also showed nucleokinesis associated with an increase of intracellular calcium, [Ca2+]i Calcium elevation was greatest in the proximal region of the leading process, a zone with a wide distribution of γ-tubulin. General increases in [Ca2+]i elicited by microperfussion with neurotrans-mitters did not elicit nucleokinesis. These results show that tangen-tial migration uses nucleokinesis, a cell-intrinsic...
Polarized Increase of Calcium and Nucleokinesis in Tangentially Migrating Neurons
Cerebral Cortex, 2004
Cortical interneurons originate from the ganglionic eminences and reach their final position in the cortex via tangential migratory routes. The mechanisms of this migration are poorly understood. Here we have performed confocal time-lapse analysis of cell movement in the intermediate zone of embryonic mouse cortical slices in order to directly visualize their mode of migration. Tangentially migrating neurons moved by nucleokinesis, characterized by active phases of discontinuous advances of the nucleus followed by periods of quiescence. Dissociated cells from the ganglionic eminences also showed nucleokinesis associated with an increase of intracellular calcium, [Ca 2+ ] i Calcium elevation was greatest in the proximal region of the leading process, a zone with a wide distribution of γ-tubulin. General increases in [Ca 2+ ] i elicited by microperfussion with neurotransmitters did not elicit nucleokinesis. These results show that tangential migration uses nucleokinesis, a cell-intrinsic process in which calcium signalling is local, directional and highly regulated.
2012
Cells often migrate in vivo in an extracellular matrix that is intrinsically three-dimensional (3D) and the role of actin filament architecture in 3D cell migration is less well understood. Here we show that, while recently identified linkers of nucleoskeleton to cytoskeleton (LINC) complexes play a minimal role in conventional 2D migration, they play a critical role in regulating the organization of a subset of actin filament bundlesthe perinuclear actin cap-connected to the nucleus through Nesprin2giant and Nesprin3 in cells in 3D collagen I matrix. Actin cap fibers prolong the nucleus and mediate the formation of pseudopodial protrusions, which drive matrix traction and 3D cell migration. Disruption of LINC complexes disorganizes the actin cap, which impairs 3D cell migration. A simple mechanical model explains why LINC complexes and the perinuclear actin cap are essential in 3D migration by providing mechanical support to the formation of pseudopodial protrusions. T he roles of actin filament dynamics and network organization in conventional cell migration and morphology on flat substrates have been studied extensively 1,2. However, fibroblasts often migrate in vivo in an extracellular matrix that is intrinsically three-dimensional (3D) and the role of actin filament architecture in 3D cell migration is less well-understood 3-5. In particular, whether recently discovered connections between nucleus and cytoskeleton mediated by Linkers of the Nucleoskeleton to the Cytoskeleton (LINC) complexes 6 play any role in cell shape, cell migration, and associated protrusion activity in 3D extracellular matrices is unknown 7. This question is important since protrusion activity plays a central role in 3D migration 8,9 , as pseudopodial protrusion processes allow cells to probe the pericellular matrix, locally attach to and pull on surrounding fibers, and detach from them dynamically 10. Corresponding local remodelling of the 3D matrix, which does not occur in conventional 2D migration, is required for effective cell migration inside a 3D matrix 11. This question is also important because cells on planar substrates display a flattened fan-like morphology, while cells completely embedded in a more physiological 3D matrix environment often adopt a spindle-like morphology well suited to negotiate tight matrices 11-15. LINC complexes are protein assemblies that span the nuclear envelope and mediate physical connections between the nuclear lamina and the cytoskeleton 6. These connections are mediated by interactions between SUN (Sad1/UNC-84) domain-containing proteins and KASH (Klarsicht/ANC-1/Syne-1 homology) domain-containing proteins at the outer nuclear membrane 16-21. The down-regulation of both Sun1 and Sun2 prevents the localization of Nesprin-2 giant at the nuclear envelope 6,22. The expression of either the recombinant SUN domain of Sun1 and Sun2 within the ER lumen or the KASH domain of Nesprins (nuclear envelope spectrins; also Syne) 1, 2, and 3 results in the displacement of all Nesprins from the NE to the ER 6,22,23. The KASH domain of Nesprins 1, 2, and 3 can interact promiscuously with either Sun1 or Sun2 23. Whether Nesprins and interactions between Nesprins and Sun proteins play a role in 3D cell migration are unknown. Here we use quantitative functional live-cell assays to show that LINC complexes play a critical role in regulating 3D actin architecture in cells in 3D matrix, and mediate protrusion dynamics, which in turn drive
Nuclear actin dynamics – From form to function
FEBS Letters, 2008
Cell biological functions of actin have recently expanded from cytoplasm to nucleus, with actin implicated in such diverse processes as gene expression, transcription factor regulation and intranuclear motility. Actin in the nucleus seems to behave differently than in the cytoplasm, raising new questions regarding the molecular mechanisms by which actin functions in cells. In this review, I will discuss dynamic properties of nuclear actin that are related to its polymerization cycle and nucleocytoplasmic shuttling. By comparing the behaviour of nuclear and cytoplasmic actin and their regulators, I try to dissect the underlying differences of these equally important cellular actin pools.
Actin isoforms in the cell nucleus
Actin, a major component of the cytoplasm, is also abundant in the nucleus. Nuclear actin is involved in a variety of nuclear processes that include transcription, chromatin remodeling and intranuclear transport. While the involvement of actin in these processes has been established, it is not quite clear how the functions of actin in the nucleus are regulated. We now show that nuclear, but not cytoplasmic actin is modified by SUMO proteins, specifically by SUMO2 and SUMO3. By using a combinatorial approach of computational modeling and site directed mutagenesis, we identified the lysines at position K68 and K284 as critical sites for SUMOylation of actin and present a model of the SUMO-actin complex. We also demonstrate that SUMOylation of actin is important for the retention of actin in the nucleus. We show that mutations in actin that prevent SUMOylation lead to a rapid export of actin from the nucleus through an Exportin 1 dependent pathway that can be inhibited by Leptomycin B. In conclusion, we demonstrate the first nuclear posttranslational modification of actin and show that this modification indeed regulates some of the nuclear functions of actin.
Actomyosin contractility rotates the cell nucleus
2013
The nucleus of the eukaryotic cell functions amidst active cytoskeletal filaments, but its response to the stresses carried by these filaments is largely unexplored. We report here the results of studies of the translational and rotational dynamics of the nuclei of single fibroblast cells, with the effects of cell migration suppressed by plating onto fibronectin-coated micro-fabricated patterns. Patterns of the same area but different shapes and/or aspect ratio were used to study the effect of cell geometry on the dynamics. On circles, squares and equilateral triangles, the nucleus undergoes persistent rotational motion, while on high-aspect-ratio rectangles of the same area it moves only back and forth. The circle and the triangle showed respectively the largest and the smallest angular speed. We show that our observations can be understood through a hydrodynamic approach in which the nucleus is treated as a highly viscous inclusion residing in a less viscous fluid of orientable fi...