FAK-mediated extracellular signals are essential for interkinetic nuclear migration and planar divisions in the neuroepithelium (original) (raw)
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Interkinetic Nuclear Movement May Provide Spatial Clues to the Regulation of Neurogenesis
Molecular and Cellular Neuroscience, 2002
During the transition from S phase to mitosis, vertebrate neuroepithelial cells displace their nuclei and subsequently migrate from the basal membrane to the apical surface of the neuroepithelium, a phenomenon termed interkinetic nuclear movement (INM). Here we provide evidence that cycling neuroepithelial cells pass through a neurogenic state in which they are situated apically, as defined by the capacity to express Notch1, Delta1, and Neurogenin2 (Ngn2). Based on this scenario, we have developed a mathematical model to analyze the influence of INM on neurogenesis. In the absence of INM, the model predicted an increase in the rate of neurogenesis due to the reduction in the influence of inhibitory signals on cells in the neurogenic state. This exacerbation in neurogenesis led to the diminished growth of the neuroepithelium and a reduction in the later production of neurons. Pharmacological perturbation of the stereotypical distribution of precursors along the orthogonal axis of the neuroepithelium resulted in an excess of neurogenesis, as seen by the expression of Ngn2, and of the neuronal marker RA4 in the retina. These findings suggest that INM might be important for the efficient and continued production of neurons in G0, since it is involved in defining a proneural cluster in the ventricular part of the neuroepithelium that contains precursors at stages of the mitotic cycle compatible with neuronal differentiation.
Regulation of Neurogenesis by Interkinetic Nuclear Migration through an Apical-Basal Notch Gradient
Cell, 2008
The different cell types in the central nervous system develop from a common pool of progenitor cells. The nuclei of progenitors move between the apical and basal surfaces of the neuroepithelium in phase with their cell cycle, a process termed interkinetic nuclear migration (INM). In the retina of zebrafish mikre oko (mok) mutants, in which the motor protein Dynactin-1 is disrupted, interkinetic nuclei migrate more rapidly and deeply to the basal side and more slowly to the apical side. We found that Notch signaling is predominantly activated on the apical side in both mutants and wild-type. Mutant progenitors are, thus, less exposed to Notch and exit the cell cycle prematurely. This leads to an overproduction of early-born retinal ganglion cells (RGCs) at the expense of later-born interneurons and glia. Our data indicate that the function of INM is to balance the exposure of progenitor nuclei to neurogenic versus proliferative signals.
Myosin II is required for interkinetic nuclear migration of neural progenitors
Proceedings of the National Academy of Sciences, 2009
Interkinetic nuclear migration (INM) is a hallmark of the polarized stem and progenitor cells in the ventricular zone (VZ) of the developing vertebrate CNS. INM is responsible for the pseudostratification of the VZ, a crucial aspect of brain evolution. The nuclear migration toward the apical centrosomes in G2 is thought to be a dynein-microtubule-based process. By contrast, the cytoskeletal machinery involved in the basally directed nuclear translocation away from the centrosome in G1 has been enigmatic. Studying the latter aspect of INM requires manipulation of the cytoskeleton without impairing mitosis and cytokinesis. To this end, we have established a culture system of mouse embryonic telencephalon that reproduces cortical development, and have applied it to explore a role of actomyosin in INM. Using the nonmuscle myosin II inhibitor blebbistatin at a low concentration at which neither cell cycle progression nor cytokinesis is impaired, we show that myosin II is required for the...
Development (Cambridge, England), 2002
The radial migration of differentiating neurons provides an essential step in the generation of laminated neocortex, although its molecular mechanism is not fully understood. We show that the protein levels of a JNK activator kinase, MUK/DLK/ZPK, and JNK activity increase potently and temporally in newly generated neurons in developing mouse telencephalon during radial migration. The ectopic expression of MUK/DLK/ZPK in neural precursor cells in utero impairs radial migration, whereas it allows these cells to leave the ventricular zone and differentiate into neural cells. The MUK/DLK/ZPK protein is associated with dotted structures that are frequently located along microtubules and with Golgi apparatus in cultured embryonic cortical cells. In COS-1 cells, MUK/DLK/ZPK overexpression impairs the radial organization of microtubules without massive depolymerization. These results suggest that MUK/DLK/ZPK and JNK regulate radial cell migration via microtubule-based events.
Neurogenesis and Neuronal Migration in the Forebrain of the TorsinA Knockout Mouse Embryo
Developmental Neuroscience, 2012
Early-onset generalized torsion dystonia, also known as DYT1 dystonia, is a childhood onset heritable neurological movement disorder involving painful, involuntary muscle contractions, sustained abnormal postures, and repetitive movements. It is caused by a GAG deletion in the Tor1A gene located on chromosome 9. TorsinA, the product of the Tor1A gene, is expressed throughout the brain beginning early in embryonic development. It plays a role in the regulation of nuclear envelope-cytoskeletal interactions, and presumably nuclear translocation. Since nuclear translocation, powered by cytoskeletal traction, is critical for cell proliferation and migration, we examined whether neurogenesis and neuronal migration are affected in Tor1A–/– mouse brain. Our data show that interkinetic nuclear migration and the pattern of migration of newly generated neurons are impaired in the dorsal forebrain of the Tor1A–/– embryo. However, neurogenesis is not altered significantly. The rate of migration ...
Neural Progenitor Nuclei IN Motion
Neuron, 2010
Interkinetic nuclear migration (INM), the movement of neuroepithelial and radial glial cell nuclei along the apical-basal axis in concert with the cell cycle, underlies the pseudostratification of the ventricular zone (VZ). Recent studies provide insight into the molecular mechanisms of INM and its effects on neural progenitor cell fate determination. Moreover, INM not only has a key role in increasing the VZ progenitor pool, but also may have set the stage for the evolution of subventricular zone progenitors implicated in cortical expansion.
Cell cycle progression is required for nuclear migration of neural progenitor cells
Brain Research, 2006
In the developing brain, neural progenitor cells in the ventricular zone (VZ) show a typical migration pattern-interkinetic nuclear migration, in which nuclear position within the VZ is correlated with the cell cycle. However, the mechanisms underlying this regulation remain unclear. To clarify whether the cell cycle progression controls nuclear migration of neural progenitor cells, we determined whether chemically induced cell cycle arrest affected nuclear migration patterns in the VZ. Administration of 5-azacytidine (5AzC) or cyclophosphamide (CP) to pregnant mice induced cell cycle arrest in the fetal neural progenitor cells of the telencephalon: 5AzC induced G2/M-phase arrest, and CP induced Sphase arrest. We used 5-bromo-2′-deoxyuridine (BrdU) labeling to determine the position of the cell in the cell cycle and the nuclei within the VZ at the same time. Cells arrested in G2/ M-phase stopped migrating in the inner area of the VZ. Cells arrested in S-phase stopped migrating in the outer area. These results indicate that nuclear position within the VZ was correlated with cell cycle phase, even when the cell cycle was disrupted, and that the nuclei of neural progenitor cells can migrate only when their cell cycle is going. Our results suggest that cell cycle regulators might control the machinery of migration through a common regulatory mechanism.
Patterns of cell division and interkinetic nuclear migration in the chick embryo hindbrain
Journal of neurobiology, 1991
Early in its development, the chick embryo hindbrain manifests an axial series of bulges, termed vhombomeres. Rhombomeres are units of cell lineage restriction, and both they and their intervening boundaries form a series that reiterates various features of neuronal differentiation, cytoarchitecture, and molecular character. The segmented nature of hindbrain morphology and cellular development may be related to early patterns of cell division. These were explored by labeling with BrdU to reveal S-phase nuclei, and staining with basic fuchsin to visualise mitotic cells. Whereas within rhombomeres, Sphase nuclei were located predominantly toward the pial surface of the neuroepithelium, at rhombomere boundaries S-phase nuclei were significantly closer to the ventricular surface. The density of mitotic figures was greater toward the centres of rhombomeres than in boundary regions. Mitotic cells did not show any consistent bias in the orientation of division, either in the centres of rhombomeres, or near boundaries. Our results are consistent with the idea that rhombomeres are centres of cell proliferation, while boundaries contain populations of relatively static cells with reduced rates of cell division.
The cytoskeletal arrangements necessary to neurogenesis
Oncotarget, 2016
During the process of neurogenesis, the stem cell committed to the neuronal cell fate starts a series of molecular and morphological changes. The understanding of the physio-pathology of mechanisms controlling the molecular and morphological changes occurring during neuronal differentiation is fundamental to the development of effective therapies for many neurologic diseases. Unfortunately, our knowledge of the biological events occurring in the cell during neuronal differentiation is still poor. In this study, we focus preliminarily on the relevance of the cytoskeletal rearrangements, which earlier drive the morphology of the neuronal precursors, and later the migrating/mature neurons. In fact, neuritogenesis, neurite branching, outgrowth and retraction are seminal to the development of a fully functional nervous system. With this in mind, we highlight the importance of iPSC technology to study the processes of cytoskeletal-driven morphological changes during neuronal differentiation.