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PubMed2002

Dual origin of the floor plate in the avian embryo.

Molecular analysis carried out on quail-chick chimeras, in which quail Hensen's node was substituted for its chick counterpart at the five- to six-somite stage (ss), showed that the floor plate of the avian neural tube is composed of distinct areas: (1) a median one (medial floor plate or MFP) derived from Hensen's node and characterised by the same gene expression pattern as the node cells (i.e. expression of HNF3beta and Shh to the exclusion of genes early expressed in the neural ectoderm such as CSox1); and (2) lateral regions that are differentiated from the neuralised ectoderm (CSox1 positive) and form the lateral floor plate (LFP). LFP cells are induced by the MFP to express HNF3beta transiently, Shh continuously and other floor-plate characteristic genes such as NETRIN: In contrast to MFP cells, LFP cells also express neural markers such as Nkx2.2 and Sim1. This pattern of avian floor-plate development presents some similarities to floor-plate formation in zebrafish embryos. We also demonstrate that, although MFP and LFP have different embryonic origins in normal development, one can experimentally obtain a complete floor plate in the neural epithelium by the inductive action of either a notochord or a MFP. The competence of the neuroepithelium to respond to notochord or MFP signals is restricted to a short time window, as only the posterior-most region of the neural plate of embryos younger than 15 ss is able to differentiate a complete floor plate comprising MFP and LFP. Moreover, MFP differentiation requires between 4 and 5 days of exposure to the inducing tissues. Under the same conditions LFP and SHH-producing cells only induce LFP-type cells. These results show that the capacity to induce a complete floor plate is restricted to node-derived tissues and probably involves a still unknown factor that is not SHH, the latter being able to induce only LFP characteristics in neuralised epithelium.

Animals↗
PubMed2006

FAK and Src kinases are required for netrin-induced tyrosine phosphorylation of UNC5.

During neuronal development, netrin and its receptors UNC5 and DCC (deleted in colorectal cancer) guide axonal growth cones in navigating to their targets. Netrin also plays important roles in the regulation of cell migration, tissue morphogenesis and tumor growth. Here, we show that netrin induces UNC5 tyrosine phosphorylation and that this effect of netrin is dependent on its co-receptor DCC. UNC5 tyrosine phosphorylation is known to be important for netrin to induce cell migration and axonal repulsion. Src tyrosine kinase activity is required for netrin to stimulate UNC5 tyrosine phosphorylation in neurons and transfected cells. The SH2 domain of Src kinase directly interacts with the cytosolic domain of UNC5 in a tyrosine-phosphorylation-dependent manner. Furthermore, the tyrosine kinase focal adhesion kinase (FAK) is also involved in netrin-induced UNC5 tyrosine phosphorylation. Both Src and FAK can phosphorylate UNC5. Our data suggest a model in which netrin stimulates UNC5 tyrosine phosphorylation and signaling in a manner dependent on the co-receptor DCC, through the recruitment of Src and FAK kinases.

Animals↗
PubMed2005

Ca2+-dependent regulation of rho GTPases triggers turning of nerve growth cones.

Cytoplasmic Ca2+ elevation and changes in Rho GTPase activity are both known to mediate axon guidance by extracellular factors, but the causal relationship between these two events has been unclear. Here we show that direct elevation of cytoplasmic Ca2+ by extracellular application of a low concentration of ryanodine, which activated Ca2+ release from intracellular stores, upregulated Cdc42/Rac, but downregulated RhoA, in cultured cerebellar granule cells and human embryonic kidney 293T cells. Chemoattractive turning of the growth cone triggered by a gradient of ryanodine was blocked by overexpression of mutant forms of Cdc42 but not of RhoA in Xenopus spinal cord neurons. Furthermore, Ca2+-induced GTPase activity correlated with activation of protein kinase C and required a basal activity of Ca2+/calmodulin-dependent protein kinase II. Thus, Rho GTPases may mediate axon guidance by linking upstream Ca2+ signals triggered by guidance factors to downstream cytoskeletal rearrangements.

Animals↗
PubMed2005

Slit-roundabout signaling neutralizes netrin-Frazzled-mediated attractant cue to specify the lateral positioning of longitudinal axon pathways.

An extending axon growth cone is subjected to attractant and repellent cues. It is not clear how these growth cones discriminate the two opposing forces and select their projection paths. Here, we report that in the Drosophila nerve cord the growth cones of longitudinal tracts are subjected to attraction by the Netrin-Frazzled pathway. However, the midline Slit neutralizes this pathway in a Robo-dependent manner and prevents Netrin-Frazzled-mediated attraction of longitudinal tracts. Our results suggest that the loss of a neutralizing effect on the Netrin-mediated attraction is responsible for the longitudinal tracts entering the midline in slit mutants as opposed to a loss of repulsion as is currently believed. This effect is not via a direct inhibition of Frazzled by Robo; instead, it is at a level downstream of Frazzled. Thus, the growth cones of longitudinal tracts subjected to two opposing forces are able to block one with the other and specify their correct lateral positioning along the midline.

Animals↗
PubMed2002

Integrins regulate responsiveness to slit repellent signals.

Integrins are concentrated within growth cones, but their contribution to axon extension and pathfinding is unclear. Genetic lesion of individual integrins does not stop growth cone extension or motility, but does increase axon defasciculation and axon tract displacement. In this study, we document a dosage-dependent phenotypic interaction between genes for the integrins, their ligands, and the midline growth cone repellent, Slit, but not for the midline attractant, Netrin. Longitudinal tract axons in Drosophila embryos doubly heterozygous for slit and an integrin gene, encoding alphaPS1, alphaPS2, alphaPS3, or betaPS1, take ectopic trajectories across the midline of the CNS. Drosophila doubly heterozygous for slit and the genes encoding the integrin ligands Laminin A and Tiggrin reveal similar errors in midline axon guidance. We propose that the strength of adhesive signaling from integrins influences the threshold of response by growth cones to repellent axon guidance cues.

Animals↗
PubMed1999

Cellular expression of a leech netrin suggests roles in the formation of longitudinal nerve tracts and in regional innervation of peripheral targets.

Netrins are secreted, diffusible proteins that direct axonal growth. To study the functions of netrins in the relatively simple and easily accessible nervous system of the leech Hirudo medicinalis, we have cloned a leech netrin and have characterized its expression during embryogenesis. By probing a leech cDNA library at low stringency with chick netrin probes, we have identified a complete cDNA clone that bears significant sequence similarity to netrins of other species. In situ hybridization and dye filling of individual neurons show that this leech netrin is expressed by several identifiable central neurons in every segmental ganglionic primordium during early stages of embryogenesis. Some of these neurons, including the bipolar cells which are thought to be involved in setting up longitudinal tracts, express this gene only transiently during embryogenesis, while others continue to express it in the adult. In addition, leech netrin is expressed by ventral but not dorsal longitudinal muscle cells in each segment before central neurons project their axons to the periphery. These highly specific expression patterns are consistent with the hypothesis that leech netrin plays a role in forming the major interganglionic neuronal tracts and in defining ventral versus dorsal domains of peripheral innervation.

Amino Acid Sequence↗
PubMed2000

Attraction vs. repulsion: the growth cone decides.

Axons are guided through their environment in response to signals provided by extracellular cues. These cues are transduced into motile responses by the tip of the growing axon, the growth cone, and can be either repulsive or attractive in nature. Recent studies have suggested that how an axon responds to any given signal depends on the internal state of the growth cone. This review discusses these studies and their importance for understanding how nerve connections are made in the developing embryo.

Animals↗
PubMed2000

Cellular mechanisms of netrin function: long-range and short-range actions.

Netrins are secreted proteins that direct axon extension and cell migration during neural development. They are bifunctional cues that act as an attractant for some cell types and as a repellent for others. Several lines of evidence suggest that two classes of receptors, the deleted in colorectal cancer (DCC) family and the UNC-5 family, mediate the attractant and repellent response to netrin. Although netrins were first identified as diffusible long-range cues for developing axons, recent findings provide evidence that they also function as short-range cues close to the surface of the cells that produce them. This short-range function of netrin contributes to guiding neurite outgrowth and mediating cell-cell interactions during development and perhaps also in adults.

Animals↗
PubMed2002

Growth cone turning induced by direct local modification of microtubule dynamics.

Pathfinding by nerve growth cones depends on attractive and repulsive turning in response to a variety of guidance cues. Here we present direct evidence to demonstrate an essential and instructive role for microtubules (MTs) in growth cone steering. First, both growth cone attraction and repulsion induced by diffusible cues in culture can be completely blocked by low concentrations of drugs that specifically inhibit dynamic microtubule ends in the growth cone. Second, direct focal photoactivated release of the microtubule-stabilizing drug taxol on one side of the growth cone consistently induces attraction (turning toward the site of application). Using the focal pipette application method, we also show that local MT stabilization by taxol induces growth cone attraction, whereas local MT destabilization by the microtubule-disrupting drug nocodazole induces repulsion (turning away). Finally, the microtubule-initiated attractive turning requires the participation of the actin cytoskeleton: local microtubule stabilization induces preferential protrusion of lamellipodia before the attractive turning, and the attraction can be abolished by inhibition of either actin polymerization or the Rho family GTPases. Together, these results demonstrate a novel steering mechanism for growth cones in which local and selective modification of dynamic microtubules can initiate and instruct directional steering. With the subsequent concerted activity of the actin cytoskeleton, this microtubule-initiated mechanism provides the growth cone with the additional means to efficiently navigate through its environment.

Actins↗
PubMed2002

The netrin 1 receptors Unc5h3 and Dcc are necessary at multiple choice points for the guidance of corticospinal tract axons.

Migrating axons require the correct presentation of guidance molecules, often at multiple choice points, to find their target. Netrin 1, a bifunctional cue involved in both attracting and repelling axons, is involved in many cell migration and axon pathfinding processes in the CNS. The netrin 1 receptor DCC and its Caenorhabditis elegans homolog UNC-40 have been implicated in directing the guidance of axons toward netrin sources, whereas the C. elegans UNC-6 receptor, UNC-5 is necessary for migrations away from UNC-6. However, a role of vertebrate UNC-5 homologs in axonal migration has not been demonstrated. We demonstrate that the Unc5h3 gene product, shown previously to regulate cerebellar granule cell migrations, also controls the guidance of the corticospinal tract, the major tract responsible for coordination of limb movements. Furthermore, we show that corticospinal tract fibers respond differently to loss of UNC5H3. In addition, we observe corticospinal tract defects in mice homozygous for a spontaneous mutation that truncates the Dcc transcript. Postnatal day 0 netrin 1 mutant mice also demonstrate corticospinal tract abnormalities. Last, interactions between the Dcc and Unc5h3 mutations were observed in gene dosage experiments. This is the first evidence of an involvement in axon guidance for any member of the vertebrate unc-5 family and confirms that both the cellular and axonal guidance functions of C. elegans unc-5 have been conserved in vertebrates.

Animals↗
PubMed2003

[Neurosurgical Embryology. Part 3: Molecular control of corpus callosum development].

The corpus callosum is the most important cerebral commissure allowing axonal fibres to cross the midline. Corpus callosum agenesis is an important condition in man that can reveal numerous genetic syndromes. The corpus callosum develops from the commissural plate, a dorsal region of the telencephalon. Then, axons growing from pyramidal neurons of cortical layer III extend and cross the midline. In experimental models, it is possible to decipher two conditions in which the development of the corpus callosum is impaired. The first condition is characterized by an impairment of the formation of the roof of the telencephalon (the primordium of the commissural plate). This condition can be explained by an abortive induction of this region by an impairment of BMP signaling. This can generate all the forms of holoprosencephaly. Other forms are due to a defective gene coding Hesx1, a transcription factor involved in the control of telencephalic morphogenesis. Such a genetic defect can be observed in human dominant forms of septo-optic dysplasia. The second condition is explained by an impairment of the molecular control of axon growth: such is the case for the couple netrin 1 and DCC or for the adhesion molecule L1.

Agenesis of Corpus Callosum↗
PubMed2004

Neurobiology: New connections between integrins and axon guidance.

Axon guidance molecules such as netrins, semaphorins, Slits and ephrins provide the cues required for accurate patterning of axonal projections in the nervous system. Recent reports have described multiple paradigms by which these molecules interact with integrin adhesion receptors in and outside the neuronal tissues.

Axons↗
PubMed2005

Netrin-integrin signaling in epithelial morphogenesis, axon guidance and vascular patterning.

Netrins and their classical receptors--DCC and neogenin--play key roles in neuronal guidance. Recent developments identify new roles for netrins in epithelial and vascular morphogenesis. Netrins accomplish these effects, at least in part, through binding to integrins and/or activating integrin-associated kinases such as FAK and Fyn. Here we discuss these recent findings and propose that integrins and classical netrin receptors cooperate to regulate multiple aspects of development.

Animals↗