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Cellular and Molecular Mechanism of Neuronal Migration

美國哥倫比亞大學(Columbia University)新聞報導我們的發現...> HOT!!!

腦皮質(cerebral cortex)在發育過程中,位於腦室區(ventricular zone)之神經幹細胞(radial glial cell)分裂生成新生的神經細胞,新生的神經細胞沿著radial glia fiber遷移,往外層皮質移動並成熟,進而發展出結構分明的大腦皮質。當神經細胞遷移時,前導突起(leading process)首先膨大,中心粒接著進入膨大處,再帶動細胞本體,最後細胞後端收縮推動細胞核 (下圖)。這個中心粒離開細胞本體的過程非常特殊,因此其機制非常值得探討。許多研究指出,若此過程發生任何差錯,則皮質結構將產生問題而導致嚴重的腦部發育疾病,例如平腦症(lissencephaly)乃由LIS1基因突變所造成,我們發現LIS1功能喪失後,神經細胞的中心粒和細胞核均無法遷移,導致神經細胞無法遷移,進而造成大腦表面平滑的發育缺陷 (Tsai et al., 2005)。

神經細胞遷移如此重要,但其機制至今卻仍未闡明。神經細胞移動時,細胞膜上的黏著蛋白與細胞外間質(extracellular matrix)產生交互作用,當神經細胞黏著後,細胞膜內的蛋白質和細胞骨架的交互作用使細胞往前遷移 (Vallee et al., 2009)。在這個過程中的物理特性為何,中心粒、細胞核、細胞骨架相互間之交互作用等過程目前仍有許多值得探討的地方。

Cells make use of a variety of mechanisms for directed migration. Recent attention has been directed at the unusual migratory behavior of a form of stem cell - the neural precursor. These cells, located at the surface of the ventricles in the developing brain, give rise to all neuronal and glial cells in the developing brain. They undergo numerous successive cycles of division to populate the forming cerebral cortex, the part of the brain responsible for cognitive function. As new cells are produced they migrate outward over considerable distances to find their proper location in the developing brain. Defects in the division of these cells can lead to microencephaly, or "small brain," and defects in migration can lead to a number of brain developmental disorders e.g., lissencephaly (smooth brain), double cortex, and periventricular heterotopia. However, how neuronal migration affects brain development and how defects in this process cause human developmental diseases in newborn infants were largely unknown.

Depending on their site of origin, neural precursors may pass through a series of morphological stages, but in each case long-distance migration involves a specific cell form which exhibits behavior not seen in the migration of non-neural cells. Existing evidence suggests that, unlike most cell types, newborn neuron moves in a strikingly discontinuous, or saltatory, manner. In these events, subcellular structures such as the cytoskeleton ("bones" of cells), the nucleus (which contains the genetic material, DNA) and other organelles ("organs" of cells) must move in a specific sequence. However, the molecular mechanisms which these organelles utilize are still unclear and the genes that are involved are largely unexplored.

Emerging evidence has indicated that the lissencephaly gene LIS1 play an essential role in neuronal migration. Previously, by live imaging of neural precursor cells in brain slices Dr. Tsai has shown that deficiencies in the LIS1 gene cause abnormalities in neuronal redistribution. These results indicated that LIS1, and presumably its regulatory target cytoplasmic dynein (a molecular motor protein), were responsible for coupling cell body movement to migration. The stage of migration in which LIS1 and cytoplasmic dynein participate is uncertain.

Our studies aim to define the subcellular events involved in neural precursor cell migration and to define the roles of dynein and LIS1 in this process. In order to elucidate the mechanism of neuronal migration and its role in causing braining developmental diseases, we used advanced molecular technologies to fluorescently label the cytoskeleton, the nucleus and other organelles in neuronal cells and monitored of the behavior of these subcellular structures in migrating neurons across live brain tissue. This research reveals a variety of novel cell behaviors and provides the first-time demonstration of the subcellular behavior of neural progenitors in the live developing brain.

We foundthat centrosomes often moved far in advance of nuclei, which exhibited extreme saltatory behavior. Inhibition of LIS1 and dynein blocked both centrosomal and nuclear movement. To gain insight into the underlying mechanisms for dynein-mediated movement, we made the first use of live microtubule imaging in living brain tissue, and observed a clear, centrosome-centered radial arrangement which persists throughout the migration cycle. In contrast to other undifferentiated cells, the distribution of neural precursor microtubules is markedly constrained by the narrow neural processes. By immunocytochemistry, we found a pronounced accumulation of dynein within the migratory process correlated with the onset of centrosomal movement. All these results have brought about a number of striking and unique features to the underlying organization and migration of neural progenitor cells, and led to a comprehensive model for how microtubule, nucleus, and dynein behavior are coordinated to affect the complex temporal and morphogenetic behavior of these cells.


Motile behavior of the centrosome (green) and the nucleus (magenta) in a migrating neuron (blue) during brain development.


Schematic diagram depicting mechanism underlying neural precursor migration. Swellings form within the migratory process possibly at sites of adhesion to the radial glial fiber (I). Dynein is recruited to the swelling, from which site it pulls on the plus ends of microtubules, resulting in forward movement of the centrosome and, presumably, the entire microtubule network (II). The trailing microtubules engage the dynein on the nuclear surface and pull the nucleus forward (III). At the same time, myosin II contracts from the rear of the soma, where it may participate in proximal axon formation and in forward nuclear movement (IV).

 

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Last updated 6/13/2013. Copyright© 2013 Jin-Wu Tsai. All rights reserved.