المؤلفون: Gujar, Mahekta R.¹, Stricker, Aubrie M.¹, Lundquist, Erik A.¹ erikl@ku.edu

المصدر: PLoS Genetics. 6/24/2019, Vol. 15 Issue 6, p1-29. 29p.

مصطلحات موضوعية: *CAENORHABDITIS elegans, *CONES, *MICROTUBULES, *GUANOSINE triphosphatase, *SPINAL cord, *CELL polarity

مستخلص: UNC-6/Netrin is a conserved axon guidance cue that directs growth cone migrations in the dorsal-ventral axis of C. elegans and in the vertebrate spinal cord. UNC-6/Netrin is expressed in ventral cells, and growth cones migrate ventrally toward or dorsally away from UNC-6/Netrin. Recent studies of growth cone behavior during outgrowth in vivo in C. elegans have led to a polarity/protrusion model in directed growth cone migration away from UNC-6/Netrin. In this model, UNC-6/Netrin first polarizes the growth cone via the UNC-5 receptor, leading to dorsally biased protrusion and F-actin accumulation. UNC-6/Netrin then regulates protrusion based on this polarity. The receptor UNC-40/DCC drives protrusion dorsally, away from the UNC-6/Netrin source, and the UNC-5 receptor inhibits protrusion ventrally, near the UNC-6/Netrin source, resulting in dorsal migration. UNC-5 inhibits protrusion in part by excluding microtubules from the growth cone, which are pro-protrusive. Here we report that the RHO-1/RhoA GTPase and its activator GEF RHGF-1 inhibit growth cone protrusion and MT accumulation in growth cones, similar to UNC-5. However, growth cone polarity of protrusion and F-actin were unaffected by RHO-1 and RHGF-1. Thus, RHO-1 signaling acts specifically as a negative regulator of protrusion and MT accumulation, and not polarity. Genetic interactions are consistent with RHO-1 and RHGF-1 acting with UNC-5, as well as with a parallel pathway, to regulate protrusion. The cytoskeletal interacting molecule UNC-33/CRMP was required for RHO-1 activity to inhibit MT accumulation, suggesting that UNC-33/CRMP might act downstream of RHO-1. In sum, these studies describe a new role of RHO-1 and RHGF-1 in regulation of growth cone protrusion by UNC-6/Netrin. [ABSTRACT FROM AUTHOR]

المؤلفون: Margaret H. Magdesian, Milena M. V. F. Carvalho, Luiz Henrique Guerreiro, Paulo José I. Beltrão, Fernando G. de Mello, Luis E. Santos, Ricardo Augusto de Melo Reis, Sergio T. Ferreira, Matthias Gralle

المصدر: PLoS ONE
PLoS ONE, Vol 6, Iss 7, p e22857 (2011)

مصطلحات موضوعية: Gene isoform, Phage display, animal structures, Protein Conformation, Science, Growth Cones, Peptide, Chick Embryo, Biology, Kidney, Signaling Pathways, Amyloid beta-Protein Precursor, Semaphorin, Developmental Neuroscience, Peptide Library, Ganglia, Spinal, Amyloid precursor protein, Animals, Humans, Immunoprecipitation, Peptide library, Cells, Cultured, chemistry.chemical_classification, Multidisciplinary, Neuronal Morphology, SEMA3A, Semaphorin-3A, Molecular biology, Peptide Fragments, Cell biology, Axon Guidance, chemistry, Ectodomain, Cellular Neuroscience, Culture Media, Conditioned, biology.protein, Medicine, Molecular Neuroscience, Research Article, Neuroscience

الوصف: The amyloid precursor protein (APP) is well known for giving rise to the amyloid-β peptide and for its role in Alzheimer's disease. Much less is known, however, on the physiological roles of APP in the development and plasticity of the central nervous system. We have used phage display of a peptide library to identify high-affinity ligands of purified recombinant human sAPPα(695) (the soluble, secreted ectodomain from the main neuronal APP isoform). Two peptides thus selected exhibited significant homologies with the conserved extracellular domain of several members of the semaphorin (Sema) family of axon guidance proteins. We show that sAPPα(695) binds both purified recombinant Sema3A and Sema3A secreted by transfected HEK293 cells. Interestingly, sAPPα(695) inhibited the collapse of embryonic chicken (Gallus gallus domesticus) dorsal root ganglia growth cones promoted by Sema3A (K(d)≤8·10(-9) M). Two Sema3A-derived peptides homologous to the peptides isolated by phage display blocked sAPPα binding and its inhibitory action on Sema3A function. These two peptides are comprised within a domain previously shown to be involved in binding of Sema3A to its cellular receptor, suggesting a competitive mechanism by which sAPPα modulates the biological action of semaphorins.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::d950d1b54106c7f2322b500bb247a7bbTest
http://europepmc.org/articles/PMC3146505Test