Role of Unc51.1 and its binding partners in CNS axon outgrowth. Genes Dev

Laboratory of Developmental Neurobiology, The Rockefeller University, New York, New York 10021-6399, USA.
Genes & Development (Impact Factor: 10.8). 04/2004; 18(5):541-58. DOI: 10.1101/gad.1151204
Source: PubMed


Previous studies showed that the serine/threonine kinase Unc51.1 is one of the earliest genes in neuronal differentiation and is required for granule cell axon formation. To examine the mechanism of Unc51.1 regulation of axon extension, we have identified two direct binding partners. The first, SynGAP, a negative regulator of Ras, is expressed within axons and growth cones of developing granule cells. Overexpression of SynGAP blocks neurite outgrowth by a mechanism that involves Ras-like GTPase cascade. The second binding partner is a PDZ domain-containing scaffolding protein, Syntenin, that binds Rab5 GTPase, the activity of which is attenuated by SynGAP. Thus, our results demonstrate that the Unc51.1-containing protein complex governs axon formation via Ras-like GTPase signaling and through regulation of the Rab5-mediated endocytic pathways within developing axons.

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    • "Where and how such collaboration occurs remains to be determined. An intriguing possibility is the endocytic pathway, as Ulk1 and Ulk2 localise to vesicular structures in growth cones and regulate neuronal process extension through early endosome trafficking at nascent neurites (Tomoda et al., 2004; Zhou et al., 2007; Toda et al., 2008), whereas zebrafish Daam1a is actively transported to endocytic vesicles and its asymmetric subcellular localisation appears to be relevant for the convergent-extension movements of notochordal cells (Kida et al., 2007). "
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    ABSTRACT: Although progress has been made in resolving the genetic pathways that specify neuronal asymmetries in the brain, little is known about genes that mediate the development of structural asymmetries between neurons on left and right. In this study, we identify daam1a as an asymmetric component of the signalling pathways leading to asymmetric morphogenesis of the habenulae in zebrafish. Daam1a is a member of the Formin family of actin-binding proteins and the extent of Daam1a expression in habenular neuron dendrites mirrors the asymmetric growth of habenular neuropil between left and right. Local loss and gain of Daam1a function affects neither cell number nor subtype organisation but leads to a decrease or increase of neuropil, respectively. Daam1a therefore plays a key role in the asymmetric growth of habenular neuropil downstream of the pathways that specify asymmetric cellular domains in the habenulae. In addition, Daam1a mediates the development of habenular efferent connectivity as local loss and gain of Daam1a function impairs or enhances, respectively, the growth of habenular neuron terminals in the interpeduncular nucleus. Abrogation of Daam1a disrupts the growth of both dendritic and axonal processes and results in disorganised filamentous actin and α-tubulin. Our results indicate that Daam1a plays a key role in asymmetric habenular morphogenesis mediating the growth of dendritic and axonal processes in dorsal habenular neurons.
    Development 10/2013; 140(19):3997-4007. DOI:10.1242/dev.091934 · 6.46 Impact Factor
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    • "Metrn (Meteorin) is a secreted protein that regulates glial cell differentiation and promotes axonal extension [56] whereas the calcineurin/NFAT signalling pathway is a key player in axonal growth and guidance (for a review, see [57]). Limk1 regulates actin filament assembly at the tip of the growth cone [58], [59] and is critical for calcium signal-induced neurite outgrowth [60] while Ulk2 triggers filopodia extension and neurite branching [61], [62]. "
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    ABSTRACT: Previously, we demonstrated i) that ergocalciferol (vitamin D2) increases axon diameter and potentiates nerve regeneration in a rat model of transected peripheral nerve and ii) that cholecalciferol (vitamin D3) improves breathing and hyper-reflexia in a rat model of paraplegia. However, before bringing this molecule to the clinic, it was of prime importance i) to assess which form - ergocalciferol versus cholecalciferol - and which dose were the most efficient and ii) to identify the molecular pathways activated by this pleiotropic molecule. The rat left peroneal nerve was cut out on a length of 10 mm and autografted in an inverted position. Animals were treated with either cholecalciferol or ergocalciferol, at the dose of 100 or 500 IU/kg/day, or excipient (Vehicle), and compared to unlesioned rats (Control). Functional recovery of hindlimb was measured weekly, during 12 weeks, using the peroneal functional index. Ventilatory, motor and sensitive responses of the regenerated axons were recorded and histological analysis was performed. In parallel, to identify the genes regulated by vitamin D in dorsal root ganglia and/or Schwann cells, we performed an in vitro transcriptome study. We observed that cholecalciferol is more efficient than ergocalciferol and, when delivered at a high dose (500 IU/kg/day), cholecalciferol induces a significant locomotor and electrophysiological recovery. We also demonstrated that cholecalciferol increases i) the number of preserved or newly formed axons in the proximal end, ii) the mean axon diameter in the distal end, and iii) neurite myelination in both distal and proximal ends. Finally, we found a modified expression of several genes involved in axogenesis and myelination, after 24 hours of vitamin supplementation. Our study is the first to demonstrate that vitamin D acts on myelination via the activation of several myelin-associated genes. It paves the way for future randomised controlled clinical trials for peripheral nerve or spinal cord repair.
    PLoS ONE 05/2013; 8(5):e65034. DOI:10.1371/journal.pone.0065034 · 3.23 Impact Factor
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    • "induced cohesiveness of epidermal stem cells through direct interaction of Delta1 with MDA-9/syntenin that maintains Delta1 on the cell surface (Estrach et al. 2007). Moreover, MDA-9/syntenin is involved in synaptic transmission via interaction with glutamate receptors, and axonal outgrowth by interacting with Unc51.1 and Rab5 (Hirbec et al. 2002; Enz and Croci 2003; Tomoda et al. 2004). "
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    ABSTRACT: Melanoma differentiation associated gene-9 (MDA-9)/syntenin is a PDZ domain-containing adaptor protein involved in multiple diverse cellular processes including organization of protein complexes in the plasma membrane, intracellular trafficking and cell surface targeting, synaptic transmission, and cancer metastasis. In the present study, we analyzed the expression pattern of MDA-9/syntenin during mouse development. MDA-9/syntenin was robustly expressed with tight regulation of its temporal and spatial expression during fetal development in the developing skin, spinal cord, heart, lung and liver, which are regulated by multiple signaling pathways in the process of organogenesis. Recent studies also indicate that MDA-9/syntenin is involved in the signaling pathways crucial during development such as Wnt, Notch and FGF. Taken together, these results suggest that MDA-9/syntenin may play a prominent role during normal mouse development in the context of cell proliferation as well as differentiation through modulating multiple signaling pathways as a crucial adaptor protein. Additionally, temporal regulation of MDA-9/syntenin expression may be required during specific stages and in specific tissues during development.
    Journal of molecular histology 11/2012; 44(2). DOI:10.1007/s10735-012-9468-1 · 1.82 Impact Factor
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