The neuronal repellent Slit inhibits leukocyte chemotaxis induced by chemotactic factors

Migration is a basic feature of many cell types in a wide range of species. Since the 1800s, cell migration has been proposed to occur in the nervous and immune systems, and distinct molecular cues for mammalian neurons and leukocytes have been identified. Here we report that Slit, a secreted protein previously known for its role of repulsion in axon guidance and neuronal migration, can also inhibit leukocyte chemotaxis induced by chemotactic factors. Slit inhibition of the chemokine-induced chemotaxis can be reconstituted by the co-expression of a chemokine receptor containing seven transmembrane domains and Roundabout (Robo), a Slit receptor containing a single transmembrane domain. Thus, there is a functional interaction between single and seven transmembrane receptors. Our results reveal the activity of a neuronal guidance cue in regulating leukocyte migration and indicate that there may be a general conservation of guidance mechanisms underlying metazoan cell migration. In addition, we have uncovered an inhibitor of leukocyte chemotaxis, and propose a new therapeutic approach to treat diseases involving leukocyte migration and chemotactic factors.     

Gap junction adhesion is necessary for radial migration in the neocortex

Radial glia, the neuronal stem cells of the embryonic cerebral cortex, reside deep within the developing brain and extend radial fibres to the pial surface, along which embryonic neurons migrate to reach the cortical plate. Here we show that the gap junction subunits connexin 26 (Cx26) and connexin 43 (Cx43) are expressed at the contact points between radial fibres and migrating neurons, and acute downregulation of Cx26 or Cx43 impairs the migration of neurons to the cortical plate. Unexpectedly, gap junctions do not mediate neuronal migration by acting in the classical manner to provide an aqueous channel for cell-cell communication. Instead, gap junctions provide dynamic adhesive contacts that interact with the internal cytoskeleton to enable leading process stabilization along radial fibres as well as the subsequent translocation of the nucleus. These results indicate that gap junction adhesions are necessary for glial-guided neuronal migration, raising the possibility that the adhesive properties of gap junctions may have an important role in other physiological processes and diseases associated with gap junction function.     

Myosin I is located at the leading edges of locomoting Dictyostelium amoebae

Movement of a eukaryotic cell along a substrate occurs by extension of lamellipodia and pseudopodia at the anterior and retraction at the posterior of the cell. The molecular and structural mechanisms of these movements are uncertain. Dictyostelium discoideum contains two forms of myosin. Here we show by immunofluorescence microscopy that non-filamentous myosin I occurs at the leading edges of the lamellipodial projections of migrating Dictyostelium amoebae, which are devoid of myosin II, whereas filamentous myosin II is concentrated in the posterior of the cells. On the basis of these locations of the two forms of myosin and their known biochemical and biophysical properties, we suggest that actomyosin I may contribute to the forces that cause extension at the leading edge of a motile cell, while the contraction of actomyosin II at the rear squeezes the cell mass forward. Myosin I isozymes might have similar roles in metazoan cells, for example at the leading edges of neuronal growth cones, and in the extension of lamellipodia and pseudopodia of leukocytes, macrophages and fibroblasts.     

A C. elegans Ror receptor tyrosine kinase regulates cell motility and asymmetric cell division.

Ror kinases are a family of orphan receptors with tyrosine kinase activity that are related to muscle specific kinase (MuSK), a receptor tyrosine kinase that assembles acetylcholine receptors at the neuromuscular junction. Although the functions of Ror kinases are unknown, similarities between Ror and MuSK kinases have led to speculation that Ror kinases regulate synaptic development. Here we show that the Caenorhabditis elegans gene cam-1 encodes a member of the Ror kinase family that guides migrating cells and orients the polarity of asymmetric cell divisions and axon outgrowth. We find that tyrosine kinase activity is required for some of the functions of CAM-1, but not for its role in cell migration. CAM-1 is expressed in cells that require its function, and acts cell autonomously in migrating neurons. Overexpression and loss of cam-1 function result in reciprocal cell-migration phenotypes, indicating that levels of CAM-1 influence the final positions of migrating cells. Our results raise the possibility that Ror kinases regulate cell motility and asymmetric cell division in organisms as diverse as nematodes and mammals.     

DISC1-dependent switch from progenitor proliferation to migration in the developing cortex

Regulatory mechanisms governing the sequence from progenitor cell proliferation to neuronal migration during corticogenesis are poorly understood. Here we report that phosphorylation of DISC1, a major susceptibility factor for several mental disorders, acts as a molecular switch from maintaining proliferation of mitotic progenitor cells to activating migration of postmitotic neurons in mice. Unphosphorylated DISC1 regulates canonical Wnt signalling via an interaction with GSK3β, whereas specific phosphorylation at serine 710 (S710) triggers the recruitment of Bardet-Biedl syndrome (BBS) proteins to the centrosome. In support of this model, loss of BBS1 leads to defects in migration, but not proliferation, whereas DISC1 knockdown leads to deficits in both. A phospho-dead mutant can only rescue proliferation, whereas a phospho-mimic mutant rescues exclusively migration defects. These data highlight a dual role for DISC1 in corticogenesis and indicate that phosphorylation of this protein at S710 activates a key developmental switch.     

Slit-Robo信号通路在心血管发育中的作用

近期研究表明, Slit-Robo信号通路对心血管系统的发育和再生发挥了重要功能. Slit3作为促血管新生因子, 能够与其受体Robo4结合, 通过RhoGTPase信号通路调控多个生理和病理过程中的血管新生. Slit3-Robo4信号通路的激活能够促进工程组织中血管网络的形成. 硫酸乙酰肝素通过Slit3-Robo4通路能够调节膈肌发育及其血管新生. Slit-Robo信号通路还参与调控心脏系统静脉回流和心包膜的发育. Slit3的缺失会导致小鼠发育过程中的肾脏缺失和输尿管发育不全. 因此, 进一步研究Slit3-Robo4信号通路对于阐释心血管系统发育和疾病的病因具有重要理论意义, 有望为心血管疾病的预防和治疗提供有力的药物作用靶点, 促进有效药物的开发.     

Corridors of migrating neurons in the human brain and their decline during infancy

The subventricular zone of many adult non-human mammals generates large numbers of new neurons destined for the olfactory bulb. Along the walls of the lateral ventricles, immature neuronal progeny migrate in tangentially oriented chains that coalesce into a rostral migratory stream (RMS) connecting the subventricular zone to the olfactory bulb. The adult human subventricular zone, in contrast, contains a hypocellular gap layer separating the ependymal lining from a periventricular ribbon of astrocytes. Some of these subventricular zone astrocytes can function as neural stem cells in vitro, but their function in vivo remains controversial. An initial report found few subventricular zone proliferating cells and rare migrating immature neurons in the RMS of adult humans. In contrast, a subsequent study indicated robust proliferation and migration in the human subventricular zone and RMS. Here we find that the infant human subventricular zone and RMS contain an extensive corridor of migrating immature neurons before 18 months of age but, contrary to previous reports, this germinal activity subsides in older children and is nearly extinct by adulthood. Surprisingly, during this limited window of neurogenesis, not all new neurons in the human subventricular zone are destined for the olfactory bulb--we describe a major migratory pathway that targets the prefrontal cortex in humans. Together, these findings reveal robust streams of tangentially migrating immature neurons in human early postnatal subventricular zone and cortex. These pathways represent potential targets of neurological injuries affecting neonates.     

Spatiotemporal dynamics of RhoA activity in migrating cells

Rho family GTPases regulate the actin and adhesion dynamics that control cell migration. Current models postulate that Rac promotes membrane protrusion at the leading edge and that RhoA regulates contractility in the cell body. However, there is evidence that RhoA also regulates membrane protrusion. Here we use a fluorescent biosensor, based on a novel design preserving reversible membrane interactions, to visualize the spatiotemporal dynamics of RhoA activity during cell migration. In randomly migrating cells, RhoA activity is concentrated in a sharp band directly at the edge of protrusions. It is observed sporadically in retracting tails, and is low in the cell body. RhoA activity is also associated with peripheral ruffles and pinocytic vesicles, but not with dorsal ruffles induced by platelet-derived growth factor (PDGF). In contrast to randomly migrating cells, PDGF-induced membrane protrusions have low RhoA activity, potentially because PDGF strongly activates Rac, which has previously been shown to antagonize RhoA activity. Our data therefore show that different extracellular cues induce distinct patterns of RhoA signalling during membrane protrusion.     

不同区域环境条件下农户居住偏好的实证分析——基于河南省346户的农户调查

依据河南省346户农户的调查数据,从农户现居住地住宅迁移类型、农户现居住地满意度、农户未来居住意愿三方面,对不同区域环境条件下农户的居住偏好进行了比较分析.分析结果表明,农户新建住宅由村内向村外迁移是现阶段农户住宅迁移的明显特征;在农户未来迁居意愿中,本村内迁居仍是农户主要的预想迁居类型,农户乡城迁居意愿与所在村庄的通达度之间存在一定联系;农户住宅投资热情仍然较高,实际住房投资中超前消费和预支消费现象突出;不同区域环境条件下农户对其所在居住地满意度评价差异明显,区域环境条件与农户居住偏好之间存在紧密联系.     

Guidance of optic nerve fibres by N-cadherin adhesion molecules

The dendritic branches (neurites) of developing neurons migrate along specific pathways to reach their targets. It has been suggested that this migration is guided by factors present on the surface of other neurons or glial cells. The molecular nature of such factors, however, remains to be elucidated. N-cadherin is a cell-surface glycoprotein which belongs to the cadherin family of cell-cell adhesion molecules. This adhesion molecule is expressed in various neuronal cells as well as in glial cells of the central and peripheral nervous systems in vertebrate embryos and recent immunological studies suggested that N-cadherin may play a role in guiding the migration of neurites on myotubes or astrocytes. To further examine this possibility, we used a molecular-genetic approach; that is, we examined the outgrowth of chicken embryonic optic axons on monolayer cultures of Neuro 2a or L cells transfected with the complementary DNA encoding chicken N-cadherin. The data indicate that N-cadherin is used as a guide molecule for the migration of optic axons on cell surfaces.     

Ephrin Bs are essential components of the Reelin pathway to regulate neuronal migration

Coordinated migration of neurons in the developing and adult brain is essential for its proper function. The secreted glycoprotein Reelin (also known as RELN) guides migration of neurons by binding to two lipoprotein receptors, the very-low-density lipoprotein receptor (VLDLR) and apolipoprotein E receptor 2 (ApoER2, also known as LRP8). Loss of Reelin function in humans results in the severe developmental disorder lissencephaly and it has also been associated with other neurological disorders such as epilepsy, schizophrenia and Alzheimer's disease. The molecular mechanisms by which Reelin activates its receptors and controls cellular functions are largely unknown. Here we show that the neuronal guidance cues ephrin B proteins are essential for Reelin signalling during the development of laminated structures in the brain. We show that ephrin Bs genetically interact with Reelin. Notably, compound mouse mutants (Reln(+/-); Efnb3(-/-) or Reln(+/-); Efnb2(-/-)) and triple ephrin B1, B2, B3 knockouts show neuronal migration defects that recapitulate the ones observed in the neocortex, hippocampus and cerebellum of the reeler mouse. Mechanistically, we show that Reelin binds to the extracellular domain of ephrin Bs, which associate at the membrane with VLDLR and ApoER2 in neurons. Clustering of ephrin Bs leads to the recruitment and phosphorylation of Dab1 which is necessary for Reelin signalling. Conversely, loss of function of ephrin Bs severely impairs Reelin-induced Dab1 phosphorylation. Importantly, activation of ephrin Bs can rescue the reeler neuronal migration defects in the absence of Reelin protein. Together, our results identify ephrin Bs as essential components of the Reelin receptor/signalling pathway to control neuronal migration during the development of the nervous system.     

动态网络拓扑中的组件迁移机制

为了解决分布式系统中的动态负载均衡，容错，动态资源利用，隐式的颗粒度控制等问题，提出了一种透明的组件迁移技术，描述了在动态网络拓扑中有效地维持系统组件之间通信链路的组件迁移机制，同时考虑了对并发迁移情况的处理，对组件在不同文件系统中的迁移性能进行了测试和比较，提出的机制只用到较少的系统拓扑知识，在迁移过程中不阻塞进程，而只要求迁移组件本身停止计算，因而对非迁移系统组件的影响被减至最低。     

Cdc42 regulates GSK-3beta and adenomatous polyposis coli to control cell polarity

Cell polarity is a fundamental property of all cells. In higher eukaryotes, the small GTPase Cdc42, acting through a Par6-atypical protein kinase C (aPKC) complex, is required to establish cellular asymmetry during epithelial morphogenesis, asymmetric cell division and directed cell migration. However, little is known about what lies downstream of this complex. Here we show, through the use of primary rat astrocytes in a cell migration assay, that Par6-PKCzeta interacts directly with and regulates glycogen synthase kinase-3beta (GSK-3beta) to promote polarization of the centrosome and to control the direction of cell protrusion. Cdc42-dependent phosphorylation of GSK-3beta occurs specifically at the leading edge of migrating cells, and induces the interaction of adenomatous polyposis coli (Apc) protein with the plus ends of microtubules. The association of Apc with microtubules is essential for cell polarization. We conclude that Cdc42 regulates cell polarity through the spatial regulation of GSK-3beta and Apc. This role for Apc may contribute to its tumour-suppressor activity.     

A sphingosine-1-phosphate receptor regulates cell migration during vertebrate heart development

Coordinated cell migration is essential in many fundamental biological processes including embryonic development, organogenesis, wound healing and the immune response. During organogenesis, groups of cells are directed to specific locations within the embryo. Here we show that the zebrafish miles apart (mil) mutation specifically affects the migration of the heart precursors to the midline. We found that mutant cells transplanted into a wild-type embryo migrate normally and that wild-type cells in a mutant embryo fail to migrate, suggesting that mil may be involved in generating an environment permissive for migration. We isolated mil by positional cloning and show that it encodes a member of the lysosphingolipid G-protein-coupled receptor family. We also show that sphingosine-1-phosphate is a ligand for Mil, and that it activates several downstream signalling events that are not activated by the mutant alleles. These data reveal a new role for lysosphingolipids in regulating cell migration during vertebrate development and provide the first molecular clues into the fusion of the bilateral heart primordia during organogenesis of the heart.     

源外鼻状构造区油运移输导机制及对成藏的控制作用——以松辽盆地尚家地区扶杨油层为例

通过油源对比对尚家地区扶杨油层油运移机制及对成藏的控制作用进行了研究,得到三肇凹陷油区青一段源岩生成的油向尚家地区扶杨油层的运移可分为三肇凹陷油区青一段生成的油向下伏扶杨油层“倒灌”运移和三肇凹陷油区扶杨油层油向尚家侧向运移2种机制.油运移输导机制对油成藏与分布的控制作用主要表现在:(1)三肇凹陷浊区青一段源岩生成的油向下伏扶杨油层“倒灌”运移,为向尚家地区侧向运移提供了油源;(2)三肇凹陷油区青一段油向下“倒灌”运移的层位控制着尚家地区扶杨油层油分布层位;(3)三肇凹陷油区扶杨油层向尚家地区侧向运移输导通道分布控制着油富集部位.     

Targeted recycling of PECAM from endothelial surface-connected compartments during diapedesis

Leukocytes enter sites of inflammation by squeezing through the borders between endothelial cells that line postcapillary venules at that site. This rapid process, called transendothelial migration (TEM) or diapedesis, is completed within 90 s after a leukocyte arrests on the endothelial surface. In this time, the leukocyte moves in ameboid fashion across the endothelial borders, which remain tightly apposed to it during transit. It is not known how the endothelial cell changes its borders rapidly and reversibly to accommodate the migrating leukocyte. Here we show that there is a membrane network just below the plasmalemma at the cell borders that is connected at intervals to the junctional surface. PECAM-1, an integral membrane protein with an essential role in TEM, is found in this compartment and constitutively recycles evenly along endothelial cell borders. During TEM, however, recycling PECAM is targeted to segments of the junction across which monocytes are in the act of migration. In addition, blockade of TEM with antibodies against PECAM specifically blocks the recruitment of this membrane to the zones of leukocyte migration, without affecting the constitutive membrane trafficking.     

PVFS数据访问的负载平衡

分析了并行文件系统PVFS中存在负载不均衡的情况,提出了根据负载情况迁移数据或做热点的副本的负载平衡方法．描述了迁移过程中考虑到迁移代价,选取最优迁移方式．提出由执行I／O的10D节点统计负载情况并传输到元数据管理节点MGR,MGR节点实现迁移和制作副本,还要维护副本的一致性的策略．     

Induction of neurogenesis in the neocortex of adult mice

Neurogenesis normally only occurs in limited areas of the adult mammalian brain--the hippocampus, olfactory bulb and epithelium, and at low levels in some regions of macaque cortex. Here we show that endogenous neural precursors can be induced in situ to differentiate into mature neurons, in regions of adult mammalian neocortex that do not normally undergo any neurogenesis. This differentiation occurs in a layer- and region-specific manner, and the neurons can re-form appropriate corticothalamic connections. We induced synchronous apoptotic degeneration of corticothalamic neurons in layer VI of anterior cortex of adult mice and examined the fates of dividing cells within cortex, using markers for DNA replication (5-bromodeoxyuridine; BrdU) and progressive neuronal differentiation. Newly made, BrdU-positive cells expressed NeuN, a mature neuronal marker, in regions of cortex undergoing targeted neuronal death and survived for at least 28 weeks. Subsets of BrdU+ precursors expressed Doublecortin, a protein found exclusively in migrating neurons, and Hu, an early neuronal marker. Retrograde labelling from thalamus demonstrated that BrdU+ neurons can form long-distance corticothalamic connections. Our results indicate that neuronal replacement therapies for neurodegenerative disease and CNS injury may be possible through manipulation of endogenous neural precursors in situ.     

压实黄土路基中水分迁移的数值模拟

根据达西定律和质量守恒原理得到路基土中水分运动的基本方程，并以此方程作为黄土路基中水分迁移研究的理论基础。采用离心机法测定路基土的水分特征曲线，由土中水分再分布过程的原理，通过室内渗透试验得出路基土的导水参数；结合路基实测含水量来确定边界条件；应用有限元法对路基内的水分迁移规律进行数值模拟。结果表明，数值模拟结果与实测值吻合较好，能较准确地反映压实黄土路基土内的水分运动。