Please use this identifier to cite or link to this item: http://scholarbank.nus.edu.sg/handle/10635/28285
Title: Investigations on the tissue distribution, localization and functions of brain-enriched leucine-rich repeats (LRR) containing proteins AMIGO AND NgR2
Authors: CHEN YANAN
Keywords: brain-enriched LRR AMIGO NgR2
Issue Date: 23-Apr-2008
Source: CHEN YANAN (2008-04-23). Investigations on the tissue distribution, localization and functions of brain-enriched leucine-rich repeats (LRR) containing proteins AMIGO AND NgR2. ScholarBank@NUS Repository.
Abstract: Leucine-rich repeats (LRR) are protein-protein interaction domains of 20-29 amino acid residues in length, found in proteins with diverse structure and functions. An emerging group of surface proteins with an ectodomain containing LRR repeats and motifs were found to be interestingly and specifically enriched in the central nervous system (CNS). AMIGO (Amphoterin-induced gene and ORF) is a type one transmembrane protein with an ectodomain containing six LRRs, followed by a single immunoglobulin (Ig)-like domain located adjacent to the transmembrane domain. AMIGO has two paralogues, named AMIGO-2/Alivin and AMIGO-3. Immunoblot, immunohitochemical and immunofluorescence analysis with antibodies raised against the short cytoplasmic region of AMIGO showed that AMIGO protein levels are developmentally regulated and is present in multiple cell types in the brain. Primarily enriched in multiple neuronal subtypes, distinct staining signals could also be found in astrocytes and oligodendrocytes (both in tissue sections and in culture). Neuronal AMIGO is targeted to both axons and dendrites. The subdomains of AMIGOb s ectodomain, however influences its polarized targeting in primary cortical neurons. Exogenously expressed full length (AMIGO-FL) and Ig domain-deleted AMIGO (AMIGO-LRR) localize to preferably to dendrites, while a LRR-deleted (AMIGO-Ig) mutant is preferentially targeted to axons. When expressed in Neuro2A neuroblastoma cells, cell surface expression of AMIGO-Ig is immediately prominent. Both AMIGO-FL and AMIGO-LRR however assume a more intracellular morphology. Silencing of AMIGO expression for appeared to retard dendritic growth of primary cortical neurons. The Nogo-66 receptor 2 (NgR2) is a LRR containing, glycosylphosphatidyl inositol (GPI)-anchored surface protein which is a paralogue of the better known and studied Nogo-66 receptor (NgR1), which is the receptor of myelin-associated axonal growth inhibitor in adult CNS myelin. NgR1 is known to function through its association with LINGO-1, which like AMIGO, has multiple LRR repeats and a single Ig-like domain. Co-immunoprecipitation (Co-IP) experiments suggest that NgR2 also interacts with LINGO-1 as well as p75NTR, another known NgR1 co-receptor. After induction of neurite growth with retinoic acid, neurite extension and cell adhesion of Neuro2A cells co-expressing both NgR2 and LINGO-1 grown on MAG-Fc coated coverslips were greatly impaired. However, co-expression of NgR2 and a dominant-negative form of LINGO-1 have no such neurite growth inhibitory effect. Our results showed that NgR2 could transducer a neurite growth inhibitory signal by engaging LINGO-1. Collectively, work reported in this thesis sheds new light on two brain-enriched LRR domains containing proteins that have, generally, opposite effects on neurite growth. Studies along these lines would be expected to provide basic information that is clinically useful against neurological diseases.
URI: http://scholarbank.nus.edu.sg/handle/10635/28285
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