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Molecular mechanisms of cell adhesion in the nervous systemThe major focus of our laboratory is to study cell adhesion. a fundamental process that is critical for embryo development and maintenance of mature tissues. Cell adhesion molecules (CAMs) are anchored in the surface of cells and can link cells to adjacent cells and to the extracellular scaffold that surrounds cells by binding to specific receptors. In the nervous system. CAMs are important for cell adhesion as well as cell migration; both processes are critical for the formation of intricate neural networks that mediate higher brain function. Our experiments are providing a better understanding of the function of CAMs and they have implications for the design of new strategies to repair damage to the nervous. We have isolated a neuronal CAM called Ng-CAM that is expressed at the surface of neurons and is involved in neuron-glia and neuron-neuron adhesion. Cloning of cDNAs encoding Ng-CAM (and its human homologue called L1) indicated that it contains immunoglobulin-like and fibronectin-like domains extracellularly. and has a short cytoplasmic region. A combination of molecular genetic. protein chemical. and cell biological techniques are being used to identify domains in Ng-CAM/L1 that mediate binding to neurons. glial cells. and extracellular ligands including laminin and brain proteoglycans. Regions in Ng-CAM/L1 that promote neurite outgrowth in culture are being tested for activity in culture as well as in vivo using a rat model for spinal cord contusion. We are also studying a related protein called Nr-CAM that is also involved in axonal growth and guidance. We have found that Nr-CAM is a potent promoter of axonal growth for peripheral neurons but not for most central neurons. Moreover. Nr-CAM is thought to play a critical role in early stages of formation of the node of Ranvier and we have found that fragments of Nr-CAM inhibit node formation in a culture model of node development. We have prepared Nr-CAM null mice that are viable and are characterizing these mice and cells derived from them to study the functions of Nr-CAM. Another project in the lab is focusing on the role of a novel radial glial cell line called C6-R that can promote neurite growth both in culture and in vivo. Transplantation experiments are assessing the migration patterns of C6-R cells in the uninjured and contused rat spinal cord. and their ability to promote axonal growth and nerve regeneration. Molecular studies are in progress to search for factors responsible for the radial phenotype given that these cell were derived by genetic manipulation of the well known C6 cell line. Selected PublicationsChang YW, Goff LA, Li H, Kane-Goldsmith N, Tzatzalos E, Hart R, Young W, Grumet M. (2009) Rapid induction of genes associated with tissue protection and neural development in contused adult spinal cord after radial glial cell transplantation. J Neurotrauma. Mar 3. [Epub ahead of print] Ratan RR, Siddiq A, Aminova L, Langley B, McConoughey S, Karpisheva K, Lee HH, Carmichael T, Kornblum H, Coppola G, Geschwind DH, Hoke A, Smirnova N, Rink C, Roy S, Sen C, Beattie MS, Hart RP, Grumet M, Sun D, Freeman RS, Semenza GL, Gazaryan I. (2008) Small molecule activation of adaptive gene expression: tilorone or its analogs are novel potent activators of hypoxia inducible factor-1 that provide prophylaxis against stroke and spinal cord injury. Ann N Y Acad Sci. 1147:383-94. Li H, Han YR, Bi C, Davila J, Goff LA, Thompson K, Swerdel M, Camarillo C, Ricupero CL, Hart RP, Plummer MR, Grumet M. (2008) Functional differentiation of a clone resembling embryonic cortical interneuron progenitors. Dev Neurobiol. 68(14):1549-64. Saarikangas, J., J. Hakanen, P.K. Mattila, M. Grumet, M. Salminen and P. Lappalainen (2008) ABBA regulates plasma-membrane and actin dynamics to promote radial glia extension. J Cell Sci 121: 1444-54. Iseda, T., T. Okuda, N. Kane-Goldsmith, M. Mathew, S. Ahmed, Y.W. Chang, W. Young and M. Grumet (2008) Single, high-dose intraspinal injection of chondroitinase reduces glycosaminoglycans in injured spinal cord and promotes corticospinal axonal regrowth after hemisection but not contusion. J Neurotrauma 25: 334-49. Li, H., Y.W. Chang, K. Mohan, H.W. Su, C.L. Ricupero, A. Baridi, R.P. Hart and M. Grumet (2008) Activated Notch1 maintains the phenotype of radial glial cells and promotes their adhesion to laminin by upregulating nidogen. Glia 56: 646-658. Basak, S., K. Raju, J. Babiarz, N. Kane-Goldsmith, D. Koticha and M. Grumet (2007) Differential expression and functions of neuronal and glial neurofascin isoforms and splice variants during PNS development. Dev Biol 311: 408-422. Li, H. and Grumet, M. (2006) BMP and LIF signaling coordinately regulate lineage restriction of radial glia in the developing forebrain. Glia 55: 24-35. Williams SE. Grumet M. Colman DR. Henkemeyer M. Mason CA. Sakurai T. (2006) A role for Nr-CAM in the patterning of binocular visual pathways. Neuron. 50(4):535-47. Koticha D. Maurel P. Zanazzi G. Kane-Goldsmith N. Basak S. Babiarz J. Salzer J. Grumet M. (2006) Neurofascin interactions play a critical role in clustering sodium channels. ankyrin G and betaIV spectrin at peripheral nodes of Ranvier. Dev Biol. 293(1):1-12. Falk J. Bechara A. Fiore R. Nawabi H. Zhou H. Hoyo-Becerra C. Bozon M. Rougon G. Grumet M. Puschel AW. Sanes JR. Castellani V. (2005) Dual functional activity of semaphorin 3B is required for positioning the anterior commissure. Neuron. 48(1):63-75. Ishiguro H. Liu QR. Gong JP. Hall FS. Ujike H. Morales M. Sakurai T. Grumet M. Uhl GR. (2006) NrCAM in addiction vulnerability: positional cloning. drug-regulation. haplotype-specific expression. and altered drug reward in knockout mice. Neuropsychopharmacology. 31(3):572-84. Koticha D. Babiarz J. Kane-Goldsmith N. Jacob J. Raju K. Grumet M. (2005) Cell adhesion and neurite outgrowth are promoted by neurofascin NF155 and inhibited by NF186. Mol Cell Neurosci. 30(1):137-48. Hasegawa. K.. Chang. Y.-W.. Li. H.. Berlin. Y. Ikeda. O.. Kane-Goldsmith. and Grumet. M. (2005) Embryonic radial glia bridge spinal cord lesions and promote functional recovery following spinal cord injury Exp. Neurol. 193: 394-410. Hafidi A. Grumet M. Sanes DH. (2004) In vitro analysis of mechanisms underlying age-dependent failure of axon regeneration.J Comp Neurol.470(1):80-92. Custer AW. Kazarinova-Noyes K. Sakurai T. Xu X. Simon W. Grumet M. Shrager P. (2003) The role of the ankyrin-binding protein NrCAM in node of Ranvier formation. J Neurosci. 23(31):10032-9. Roonprapunt C. Huang W. Grill R. Friedlander D. Grumet M. Chen S. Schachner M. Young W. (2003) Soluble cell adhesion molecule L1-Fc promotes locomotor recovery in rats after spinal cord injury. J Neurotrauma. 20(9):871-82. Haspel J. Grumet M. (2003) The L1CAM extracellular region: a multi-domain protein with modular and cooperative binding modes. Front Biosci. 8:s1210-25. Review. Li H. Berlin Y. Hart RP. Grumet M. (2003) Microtubules are critical for radial glial morphology: possible regulation by MAPs and MARKs. Glia. 44(1):37-46. Hasegawa K. Grumet M. (2003) Trauma-induced tumorigenesis of cells implanted into the rat spinal cord. J Neurosurg. 98(5):1065-71. |
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