The role of blood platelets in tumor angiogenesis

The purple photosynthetic bacterium Rubrivivax gelatinosus has, at least, four periplasmic electron carriers, i.e., HiPIP, two cytochromes c?with low- and high-midpoint potentials, and cytochrome c? as electron donors to the photochemical reaction center. The quadruple mutant lacking all four electron carrier proteins showed extremely slow photosynthetic growth. During the long-term cultivation of this mutant under photosynthetic conditions, a suppressor strain recovering the wild-type growth level appeared. In the cells of the suppressor strain, we found significant accumulation of a soluble c-type cytochrome that has not been detected in wild-type cells. This cytochrome c has a redox midpoint potential of about +280 mV and could function as an electron donor to the photochemical reaction center in vitro. The amino acid sequence of this cytochrome c was 65% identical to that of the high-potential cytochrome c?of this bacterium. The gene for this cytochrome c was identified as nirM on the basis of its location in the newly identified nir operon, which includes a gene coding cytochrome cd?-type nitrite reductase. Phylogenetic analysis and the well-conserved nir operon gene arrangement suggest that the origin of the three cytochromes c? in this bacterium is NirM. The two other cytochromes c?, of high and low potentials, proposed to be generated by gene duplication from NirM, have evolved to function in distinct pathways.     

Semaphorins and their receptors in olfactory axon guidance.

The mammalian olfactory system is capable of discriminating among a large variety of odor molecules and is therefore essential for the identification of food, enemies and mating partners. The assembly and maintenance of olfactory connectivity have been shown to depend on the combinatorial actions of a variety of molecular signals, including extracellular matrix, cell adhesion and odorant receptor molecules. Recent studies have identified semaphorins and their receptors as putative molecular cues involved in olfactory pathfinding, plasticity and regeneration. The semaphorins comprise a large family of secreted and transmembrane axon guidance proteins, being either repulsive or attractive in nature. Neuropilins were shown to serve as receptors for secreted class 3 semaphorins, whereas members of the plexin family are receptors for class 1 and V (viral) semaphorins. The present review will discuss a role for semaphorins and their receptors in the establishment and maintenance of olfactory connectivity.     

The role of blood flow and microRNAs in blood vessel development

The circulatory system is the first organ system that develops during embryogenesis, and is essential for embryo viability and survival. Crucial for developing a functional vasculature are the specification of arterial-venous identity in vessels and the formation of a hierarchical branched vascular network. Sprouting angiogenesis, intussusception, and flow driven remodeling events collectively contribute to establishing the vascular architecture. At the molecular level, arterial-venous identity and branching are regulated by genetically hardwired mechanisms involving Notch, vascular endothelial growth factor and neural guidance molecule signaling pathways, modulated by hemodynamic factors. MicroRNAs are small, non-coding RNAs that act as silencers to fine-tune the gene expression profile. MicroRNAs are known to influence cell fate decisions, and microRNA expression can be controlled by blood flow, thus placing microRNAs potentially at the center of the genetic cascades regulating vascular differentiation. In the present review, we summarize current progress regarding microRNA functions in blood vessel development with an emphasis on studies performed in zebrafish and mouse models.     

Slit proteins bind Robo receptors and have an evolutionarily conserved role in repulsive axon guidance

Extending axons in the developing nervous system are guided in part by repulsive cues. Genetic analysis in Drosophila, reported in a companion to this paper, identifies the Slit protein as a candidate ligand for the repulsive guidance receptor Roundabout (Robo). Here we describe the characterization of three mammalian Slit homologs and show that the Drosophila Slit protein and at least one of the mammalian Slit proteins, Slit2, are proteolytically processed and show specific, high-affinity binding to Robo proteins. Furthermore, recombinant Slit2 can repel embryonic spinal motor axons in cell culture. These results support the hypothesis that Slit proteins have an evolutionarily conserved role in axon guidance as repulsive ligands for Robo receptors.     

Models of axon guidance and bundling during development

Diffusible chemoattractants and chemorepellants, together with contact attraction and repulsion, have been implicated in the establishment of connections between neurons and their targets. Here we study how such diffusible and contact signals can be involved in the whole sequence of events from bundling of axons, guidance of axon bundles towards their targets, to debundling and the final innervation of individual targets. By means of computer simulations, we investigate the strengths and weaknesses of a number of particular mechanisms that have been proposed for these processes.     

Metalloproteases: carving out a role in axon guidance

Two families of metalloproteases, the matrix metalloproteases (MMPs) and the A Disintegrin and Metalloproteases (ADAMs), have recently been implicated in the formation of neural connections in the developing central nervous system. Invertebrate and vertebrate axons fail to extend and/or make pathfinding errors when metalloprotease function is inhibited or absent. Culture studies suggest that this requirement for metalloprotease activity results from their ability to cleave ligands, or their receptors, so as to activate or inhibit specific axon extension or guidance signaling pathways.     

A role for S1P signalling in axon guidance in the Xenopus visual system

Sphingosine 1-phosphate (S1P), a lysophospholipid, plays an important chemotactic role in the migration of lymphocytes and germ cells, and is known to regulate aspects of central nervous system development such as neurogenesis and neuronal migration. Its role in axon guidance, however, has not been examined. We show that sphingosine kinase 1, an enzyme that generates S1P, is expressed in areas surrounding the Xenopus retinal axon pathway, and that gain or loss of S1P function in vivo causes errors in axon navigation. Chemotropic assays reveal that S1P elicits fast repulsive responses in retinal growth cones. These responses require heparan sulfate, are sensitive to inhibitors of proteasomal degradation, and involve RhoA and LIM kinase activation. Together, the data identify downstream components that mediate S1P-induced growth cone responses and implicate S1P signalling in axon guidance.     

The mouse SLIT family: secreted ligands for ROBO expressed in patterns that suggest a role in morphogenesis and axon guidance.

The Slit gene encodes a secreted molecule essential for neural development in Drosophila embryos. Here we report the identification of three Slit homologues in the mouse. We demonstrate that the mouse SLIT1 protein can bind ROBO1, a transmembrane receptor implicated in axon guidance. Both whole-mount and section in situ hybridization studies reveal unique and complementary patterns of expression of the three mouse Slit genes and of Robo1, both within the central nervous system and in other developing tissues. The complementary expression patterns of Slit and Robo1 and their in vitro interaction suggest a ligand-receptor relationship. The expression of all three Slit genes in the floor plate suggests that they are likely to share the same functional properties with their Drosophila homologue in midline neural development and axon guidance. The complementary expression of Slit and Robo1 in different subdivisions of the somites suggests their possible function in axon pathfinding and neural crest cell migration. The unique expression pattern in limb and other organs indicates additional potential functions of the Slit gene family.     

Tangential neuronal migration controls axon guidance: a role for neuregulin-1 in thalamocortical axon navigation

Neuronal migration and axon guidance constitute fundamental processes in brain development that are generally studied independently. Although both share common mechanisms of cell biology and biochemistry, little is known about their coordinated integration in the formation of neural circuits. Here we show that the development of the thalamocortical projection, one of the most prominent tracts in the mammalian brain, depends on the early tangential migration of a population of neurons derived from the ventral telencephalon. This tangential migration contributes to the establishment of a permissive corridor that is essential for thalamocortical axon pathfinding. Our results also demonstrate that in this process two different products of the Neuregulin-1 gene, CRD-NRG1 and Ig-NRG1, mediate the guidance of thalamocortical axons. These results show that neuronal tangential migration constitutes a novel mechanism to control the timely arrangement of guidance cues required for axonal tract formation in the mammalian brain.     

Signaling in glial development: differentiation migration and axon guidance.

Glial cells have diverse functions that are necessary for the proper development and function of complex nervous systems. During development, a variety of reciprocal signaling interactions between glia and neurons dictate all parts of nervous system development. Glia may provide attractive, repulsive, or contact-mediated cues to steer neuronal growth cones and ensure that neurons find their appropriate synaptic targets. In fact, both neurons and glia may act as migrational substrates for one another at different times during development. Also, the exchange of trophic signals between glia and neurons is essential for the proper bundling, fasciculation, and ensheathement of axons as well as the differentiation and survival of both cell types. The growing number of links between glial malfunction and human disease has generated great interest in glial biology. Because of its relative simplicity and the many molecular genetic tools available, Drosophila is an excellent model organism for studying glial development. This review will outline the roles of glia and their interactions with neurons in the embryonic nervous system of the fly.     

Receptor protein tyrosine phosphatases regulate neural development and axon guidance

The regulation of tyrosine phosphorylation is recognized as an important developmental mechanism. Both addition and removal of phosphate moieties on tyrosine residues are tightly regulated during development. Originally, most attention focused on the role of tyrosine kinases during development, but more recently, the developmental importance of tyrosine phosphatases has been gaining interest. Receptor protein tyrosine phosphatases (RPTPs) are of particular interest to developmental biologists because the extracellular domains of RPTPs are similar to those of cell adhesion molecules (CAMs). This suggests that RPTPs may have functions in development similar to CAMs. This review focuses on the role of RPTPs in development of the nervous system in processes such as axon guidance, synapse formation, and neural tissue morphogenesis.     

The role of microenvironment in tumor angiogenesis

Tumor microenvironment is essential for tumor cell proliferation, angiogenesis, invasion and metastasis through its provision of survival signals, secretion of growth and pro-angiogenic factors, and direct adhesion molecule interactions. This review examines its importance in the induction of an angiogenic response in tumors and in multiple myeloma. The encouraging results of pre-clinical and clinical trials in which tumors have been treated by targeting the tumor microenvironment are also discussed.     

T-cadherin as a receptor regulating angiogenesis and blood vessel remodeling

The search for a membrane receptor responsible for hormone-like effects of low density lipoproteins (LDL) has revealed two proteins (Mol. wt. 105 and 130 kDa) in the membrane fraction of human aortic smooth muscle cells. These proteins were identified as mature T-cadherin and its unprocessed precursor. T-cadherin was originally cloned from chick embryo brain, where it was implicated in axon guidance in the developing nervous system. Our study on the T-cadherin distribution in human organs and tissues has indicated that T-cadherin is specifically expressed in nervous and cardiovascular system. However, physiological significance of T-cadherin expression in the vasculature, as well as intracellular signaling pathways mediating its effects remain obscure. This review summarizes our current knowledge about intracellular signaling utilized by T-cadherin and discusses possible functions of T-cadherin in the vasculature.     

Angiopoietin 1 promotes tumor angiogenesis and tumor vessel plasticity of human cervical cancer in mice

We have previously shown that following psoralen photoactivation (PUVA treatment) human dermal fibroblasts undergo long-term growth arrest as well as morphological and functional changes reminiscent of cellular senescence [ 1 ]. In the absence of molecular data on what constitutes normal senescence, it has been difficult to decide whether these PUVA-induced changes reflect cellular senescence or rather a mimic thereof. We herein report that PUVA-induced growth arrest, the senescent phenotype with long-term induction of senescence-associated beta-galactosidase, as well as increased expression of matrix metalloprotease-1 are fully reversible at days 100 to 130 post PUVA treatment in four independently tested fibroblast strains. The late returning growth capacity in PUVA-treated fibroblasts is not due to immortalization, as shown by continued lack of telomerase activity, accelerated telomere shortening, and a decrease in overall growth rates in fibroblasts in their regrowing phase post PUVA treatment. Lack of anchorage-independent growth additionally suggests that the cells are also not tumorigenically transformed. Collectively, our data suggest that PUVA-induced changes do not fully reflect replicative senescence but rather represent a long-term transient phenocopy of senescence. The model reported here is particularly suited to elucidating mechanisms underlying long-term transient growth arrest, the related functional changes, and the release of cells thereof.     

Novel mutations affecting axon guidance in zebrafish and a role for plexin signalling in the guidance of trigeminal and facial nerve axons

In zebrafish embryos, the axons of the posterior trigeminal (Vp) and facial (VII) motoneurons project stereotypically to a small number of target muscles derived from the first and second branchial arches (BA1, BA2). Use of the Islet1 (Isl1)-GFP transgenic line enabled precise real-time observations of the growth cone behaviour of the Vp and VII motoneurons within BA1 and BA2. Screening for N-ethyl-N-nitrosourea-induced mutants identified seven distinct mutations affecting different steps in the axonal pathfinding of these motoneurons. The class 1 mutations caused severe defasciculation and abnormal pathfinding in both Vp and VII motor axons before they reached their target muscles in BA1. The class 2 mutations caused impaired axonal outgrowth of the Vp motoneurons at the BA1-BA2 boundary. The class 3 mutation caused impaired axonal outgrowth of the Vp motoneurons within the target muscles derived from BA1 and BA2. The class 4 mutation caused retraction of the Vp motor axons in BA1 and abnormal invasion of the VII motor axons in BA1 beyond the BA1-BA2 boundary. Time-lapse observations of the class 1 mutant, vermicelli (vmc), which has a defect in the plexin A3 (plxna3) gene, revealed that Plxna3 acts with its ligand Sema3a1 for fasciculation and correct target selection of the Vp and VII motor axons after separation from the common pathways shared with the sensory axons in BA1 and BA2, and for the proper exit and outgrowth of the axons of the primary motoneurons from the spinal cord.