Semaphorins家族在肺发育与肺疾病中作用的研究进展

Semaphorins家族是一类经典的神经元轴突导向排斥性因子。最近大量研究表明,该家族除了在神经系统内发挥作用外,在肺发育与肺疾病中也起着重要作用。Semaphorins家族可通过调节肺泡上皮细胞、肺内皮细胞的增殖、黏附、迁移和凋亡,促进或抑制肺与血管的正常发育和病理过程。该文将对现阶段Semaphorins家族对肺发育过程中肺分支形成、血管形成和肺相关疾病作用的最新研究进展进行综述。     

Slit/Robo信号在血管新生中的功能研究

分泌型糖蛋白Slit及其受体Roundabout(Robo)最初是作为一类重要的发育中神经元轴突导向分子而被发现的。目前为止对Slit/Robo信号对神经系统发育过程中轴突吸引或排斥的导向功能研究比较多,而对在发育中生长方式与其非常相似的血管发生过程中研究比较少。现有研究提示两者在发育过程中可能存在共同的信号调控机制,是Slit/Robo信号通路在血管新生中充当着重要的角色。该文就Slit/Robo信号对血管内皮细胞迁移的调节、对血管新生的作用及其可能介导的信号通路进行综述,以期进一步推动Slit/Robo信号通路在血管发生中的研究。     

PPARγ在神经系统发育及相关疾病中的研究进展

过氧化物酶体增殖物激活受体γ (peroxisome proliferator-activated receptor gamma, PPARγ)作为配体依赖型核内转录因子,是经典的脂代谢调控因子,参与机体脂肪生成、葡萄糖代谢、血管生成和炎症发生等多种生物过程。除了在脂肪酸代谢活跃部位高水平表达, PPARγ在神经系统也大量存在,近年来越来越多的研究开始关注PPARγ在神经系统中扮演的角色。本文综述了PPARγ在神经系统发育及相关疾病发生发展中的重要作用:PPARγ通过调控机体炎症反应因子参与神经系统炎症过程;在中枢神经系统或周围神经系统发生外因损伤时, PPARγ通过抑炎或促进再生表现出神经保护功能;在帕金森病、阿尔茨海默病等神经退行性疾病中,调控PPARγ的表达可以起到延缓病程或临床治疗的效果;在视网膜病变中, PPARγ可以通过保护视网膜神经节细胞起到缓解作用。这些总结工作可以为PPARγ在神经系统发育和相关疾病进程中的调控机制研究及配体类药物开发提供参考资料。     

ROBO4 与缺血性脑血管病相关的研究进展

Roundabout(Robo)蛋白是神经轴突导向分子家族Slit蛋白的单次跨膜受体,属于一种神经细胞粘附分子。Robo蛋白在神经系统已被确认具有重要轴突导向功能。近年来研究发现,血管新生的内皮细胞表面只特异性地表达Robo4,且Robo4对内皮细胞迁移、病理性血管生成和血管完整性都具有调节作用。缺血性脑血管病是人类致残甚至死亡的主要疾病之一,由于短暂或持续的脑血流减少而造成脑细胞损伤,因此,恢复脑血流、促进血管再生对脑功能恢复至关重要。Robo4对血管方面的作用为我们进一步研究及了解其在血管生成中的机制提供重要依据,也为缺血性脑血管病的治疗提供新的发展方向。     

神经营养因子

神经营养因子(neurotrophic factor)是多肽。这些因子在发育神经系统中支持神经元生长、分化和存活;在成年神经系统中有维持神经元的作用。最近的资料还支持一种新的观点,即有些神经营养因子可能与改善脑发育中神经元之间的联系有关。在神经营养因子中,一些因子主要作用于神经元;而另一些因子既作用于神经元,也作用于非神经元。     

神经纤毛蛋白-1的研究进展

神经纤毛蛋白-1(neuropilin 1,Nrp1)是单次跨膜受体,属于Neuropilin家族。它是神经轴突导向因子3(semaphorin 3,Sema3)和血管内皮生长因子165(vascular endothelial growth factor 165,VEGF165)的特异性受体,既可调节神经系统中轴突的生长、导向和迁移,又与心血管系统的血管新生、病理性血管损伤的修复有关。另外,有大量研究表明Nrp1对肿瘤的发展起重要作用,提示Nrp1是肿瘤治疗的潜在靶点。最近,有研究发现Nrp1与肥胖诱导的胰岛素抵抗和脓毒症相关,揭示其在急、慢性炎症中的作用。我们在本文中综述了Nrp1的研究进展,以期更好的理解Nrp1在生理和病理情况下的功能。     

神经营养因子

神经营养因子是一类多肽,在神经系统的发育吕具有支持神经细胞生长,分化和生存,在成熟的神经系统中具有维持神经细胞生存与作用。在神经系统疾病中可能具有减轻或改善神经退行性改变的作用,对神经元有保护效应,并可促进神经元的再生与修复。     

神经营养因子前体蛋白功能的研究进展

神经营养因子是一组在结构与功能上具有相关性的多肽性因子,它们通过前体蛋白的切割成为具有特定功能的成熟蛋白,为不同的神经细胞亚群提供营养支持,在中枢神经系统和周围神经系统的发育分化及病理生理中起着重要的作用.以前认为神经营养因子的前体不具有生理功能,最近的研究则表明,神经营养因子前体蛋白具有不同于神经营养因子的功能.研究发现,神经营养因子前体,至少神经生长因子和脑源性神经营养因子的前体大量存在于细胞外,它们通过与p75NTR和sortilin受体组成三聚体诱导神经细胞的凋亡.这一机制可能与神经发育时调节神经细胞的比例,神经损伤后神经细胞的死亡以及某些人类疾病的发生有密切联系.此外,神经营养因子前体还可能具有其他未知的新功能,对神经营养因子前体功能的深入研究将使人们对神经系统的发生、发育及神经系统疾病的发病机制有更加深入的了解,并有助于神经系统疾病新药物、新疗法的开发与研究.     

EphrinB2/EphB4 在血管生长中的作用及中医药研究展望*

近年来,有关ephrin及其Eph受体的作用研究已从神经系统方面逐步向血管生长扩展。已有研究表明ephrinB2/EphB4及其独特的双向信号转导几乎参与血管生长的每个方面,涉及血管发育过程中的动静脉分化、胚胎后血管新生包括内皮细胞增殖、迁移、粘附和分化等过程,且与VEGF、Notch等血管新生调控因子关系密切。另外,实验表明活血化瘀名方血府逐瘀汤显著的促血管新生作用与ephrinB2/EphB4相关,说明中医药促血管新生中ephrinB2/EphB4具有重要作用。本文部分总结了ephrinB2/EphB4在血管生长中的作用,并提出中医药在这方面的展望。     

脑内皮细胞与神经干细胞共培养促进神经干细胞的迁移

近些年来,人们发现神经发生和血管发生间有着密切的联系,并逐渐开始关注内皮细胞对神经干细胞（NSCs）的影响。人们发现内皮细胞对NSCs的自我更新、分化、迁移有着重要的调节作用,而NSCs对内皮细胞也有促血管形成的作用。有研究报道,内皮细胞具有分泌VEGF、BDNF、SDF-1等因子的功能,内皮细胞是否通过其分泌的因子对NSCs的迁移进行调节,     

Navigating their way to the clinic: emerging roles for axon guidance molecules in neurological disorders and injury

The mechanisms underlying formation of the basic network of the nervous system are of fundamental interest in developmental neurobiology. During the wiring of the nervous system, newborn neurons send axons that travel long distances to their targets. These axons are directed by environmental cues, known as guidance cues, to their correct destinations. Through extensive studies in vertebrates and invertebrates many of the guidance cues and their receptors have been identified. Recently, guidance molecules have been suggested to have important roles in pathological conditions of the nervous system. Mutations in guidance receptors have been associated with hereditary neurological disorders, and deregulation of guidance cues might be associated with predisposition to epilepsy. In addition, it was suggested that guidance molecules play roles in the ability of the adult nervous system to recover and repair after injury. Thus, molecules that were first discovered as "developmental cues" are now emerging as important factors in neurological disease and injury in the adult.     

Semaphorin-neuropilin-1 interactions in plasticity and regeneration of adult neurons

During development, axonal growth cones are guided to their appropriate targets by many attractive and repulsive cues. It has become increasingly clear over the last few years that how the growth cone responds to these cues depends both on the molecular nature of the cue and on the internal state of the neuron. The unexpected result is that the same molecule can act as an attractor or as a repellent. A number of guidance cues used by neurons during development are retained in the adult nervous system, where their function is often still unclear. Most of these molecules are implicated in plasticity in the adult nervous system and can play a role (sometimes maladaptive) in neuronal regeneration after injury. A group of axonal guidance cues that has been well studied in development is the semaphorin family of secreted and membrane-anchored proteins, which has been implicated in axon steering, fasciculation, branching and synapse formation. This review focuses on semaphorin-3A (probably the best-characterized semaphorin) and its receptors (in particular neuropilin-1) in the adult nervous system and argues that semaphorin-3A plays a role in the maintenance and regeneration of adult sensory neurons.     

Planarian homologs of netrin and netrin receptor are required for proper regeneration of the central nervous system and the maintenance of nervous system architecture

Conserved axon guidance mechanisms are essential for proper wiring of the nervous system during embryogenesis; however, the functions of these cues in adults and during regeneration remain poorly understood. Because freshwater planarians can regenerate a functional central nervous system (CNS) from almost any portion of their body, they are useful models in which to study the roles of guidance cues during neural regeneration. Here, we characterize two netrin homologs and one netrin receptor family member from Schmidtea mediterranea. RNAi analyses indicate that Smed-netR (netrin receptor) and Smed-netrin2 are required for proper CNS regeneration and that Smed-netR may mediate the response to Smed-netrin2. Remarkably, Smed-netR and Smed-netrin2 are also required in intact planarians to maintain the proper patterning of the CNS. These results suggest a crucial role for guidance cues, not only in CNS regeneration but also in maintenance of neural architecture.     

Ena/VASP: proteins at the tip of the nervous system

The emergence of neurites from a symmetrical cell body is an essential feature of nervous system development. Neurites are the precursors of axons and dendrites and are tipped by growth cones, motile structures that guide elongating axons in the developing nervous system. Growth cones steer the axon along a defined path to its appropriate target in response to guidance cues. This navigation involves the dynamic extension and withdrawal of actin-filled finger-like protrusions called filopodia that continuously sample their environment. Ena/VASP proteins, a conserved family of actin-regulatory proteins, are crucial for filopodia formation and function downstream of several guidance cues. Here we review recent findings into Ena/VASP function in neurite initiation, axon outgrowth and guidance.     

Hierarchical guidance cues in the developing nervous system of C. elegans

During embryogenesis, the basic axon scaffold of the nervous system is formed by special axons that pioneer pathways between groups of cells. To find their way, the pioneer growth cones detect specific cues in their extracellular environment. One of these guidance cues is netrin. Observations and experimental manipulations in vertebrates and nematodes have shown that netrin is a bifunctional guidance cue that can simultaneously attract and repel axons. During the formation of this basic axon scaffold in Caenorhabditis elegans, the netrin UNC-6 is expressed by neuroglia and pioneer neurons, providing hierarchical guidance cues throughout the animal. Each cue has a characteristic role depending on the cell type, its position and the developmental stage. These roles include activities as global, decussation and labeled-pathway cues. This hierarchical model of UNC-6 netrin-mediated guidance suggests a method by which guidance cues can direct formation of basic axon scaffolds in developing nervous systems.     

<Emphasis Type="Italic">Drosophila</Emphasis> Dunc-115 mediates axon projection through actin binding

A central step in organizing the central nervous system development is the growth cone of an axon navigating through guidance cues to reach its specific target. While a great deal of this process has been understood especially in identifying the extracellular guidance cues and their membrane receptors, much less is known about how guidance signals are further relayed to the actin filaments that are central to the mobility of the growth cone. The previous results from our laboratory have shown that Drosophila gene dunc-115 regulates axon projection in the eye and the central nervous system. Furthermore, Dunc-115 has a villin-headpiece (VHD) domain, implying the possibility of binding to actin. To further characterize Dunc-115’s functions, we have identified the isoform Dunc-115L as a possible downstream target in relaying guidance cues further down to the cytoskeleton. Specifically, we have shown that Dunc-115 regulates neural connections in both the eye and the central nervous system in Drosophila and that Dunc-115 contains an actin-binding domain potentially capable of binding to actin filaments. In this report, we show that Dunc-115 binds to actin via its VHD domain directly, suggesting a possible mechanism for how Dunc-115 relays guidance signals.     

The role of repulsive guidance molecules in the embryonic and adult vertebrate central nervous system

During the development of the nervous system, outgrowing axons often have to travel long distances to reach their target neurons. In this process, outgrowing neurites tipped with motile growth cones rely on guidance cues present in their local environment. These cues are detected by specific receptors expressed on growth cones and neurites and influence the trajectory of the growing fibres. Neurite growth, guidance, target innervation and synapse formation and maturation are the processes that occur predominantly but not exclusively during embryonic or early post-natal development in vertebrates. As a result, a functional neural network is established, which is usually remarkably stable. However, the stability of the neural network in higher vertebrates comes at an expensive price, i.e. the loss of any significant ability to regenerate injured or damaged neuronal connections in their central nervous system (CNS). Most importantly, neurite growth inhibitors prevent any regenerative growth of injured nerve fibres. Some of these inhibitors are associated with CNS myelin, others are found at the lesion site and in the scar tissue. Traumatic injuries in brain and spinal cord of mammals induce upregulation of embryonic inhibitory or repulsive guidance cues and their receptors on the neurites. An example for embryonic repulsive directional cues re-expressed at lesion sites in both the rat and human CNS is provided with repulsive guidance molecules, a new family of directional guidance cues.     

Semaphorins: a new class of immunoregulatory molecules

The immune and nervous systems play distinct roles in maintaining physiological homeostasis. Recent data indicates that these systems influence one another and share many proteins and pathways that are essential for their normal function and development. Molecules originally shown to be critical for the development of proper immune responses have recently been found to function in the nervous system. Conversely, neuronal guidance cues can modulate immune functions. Although semaphorins were originally identified as axon guidance factors active during neuronal development, several recent studies have identified indispensable functions for these molecules in the immune system. This review provides an overview of the rapidly emerging functions of semaphorins and their receptors in the immune system.     

Growth and guidance cues for regenerating axons: where have they gone?

Both attractive and repellent cues are required to guide developing axons to their targets in the central nervous system. Critical guidance molecules in the developing brain include the semaphorins, netrins, slits, and ephrins. Current research indicates that many of these molecules and their receptors are expressed in the adult central nervous system (CNS), and that injury can alter the levels of these ligands/receptors. Recent studies have begun the process of elucidating the functions of these receptors in adult mammals, and the effects that they have on the regeneration of adult neurons. This review addresses our current knowledge with respect to the response of adult CNS neurons to axonal injury, interventions for enhancing the survival and regeneration of injured neurons, and the expression of developmental axon guidance cues in the injured mature CNS, with specific focus on the retino-tectal projection.     

Regulation of axonal outgrowth and pathfinding by integrin-ECM interactions

Developing neurons use a combination of guidance cues to assemble a functional neural network. A variety of proteins immobilized within the extracellular matrix (ECM) provide specific binding sites for integrin receptors on neurons. Integrin receptors on growth cones associate with a number of cytosolic adaptor and signaling proteins that regulate cytoskeletal dynamics and cell adhesion. Recent evidence suggests that soluble growth factors and classic axon guidance cues may direct axon pathfinding by controlling integrin-based adhesion. Moreover, because classic axon guidance cues themselves are immobilized within the ECM and integrins modulate cellular responses to many axon guidance cues, interactions between activated receptors modulate cell signals and adhesion. Ultimately, growth cones control axon outgrowth and pathfinding behaviors by integrating distinct biochemical signals to promote the proper assembly of the nervous system. In this review, we discuss our current understanding how ECM proteins and their associated integrin receptors control neural network formation.