The CRMP proteins were originally defined as mediators of Sema3A signaling and neuronal differentiation. transducing the signal into the cell via its large intracellular CHR2797 cost domain. Although the effect of Sema3A on growth cones was first described nearly 15 years ago, the intracellular signaling pathways that lead to the cellular effects have only recently begun to be comprehended. Monomeric G-proteins, various kinases, the redox protein, MICAL, and protein turnover have all been implicated in PlexA transduction. In addition, the collapsin-response-mediator protein (CRMP) family of cytosolic phosphoproteins plays a crucial role in Sema3A/NP1/PlexA signal transduction. Current knowledge regarding CRMP functions are reviewed here. Properties and Expression of CRMPs A number of CRMP genes were identified independently in different species around the same time, and were named according to their method of discovery. CRMPs are also known as turned on after division (TOAD-64),5 dihydropyrimidinase related protein (DRP),6 unc33 like protein (Ulip),7 and TUC (TOAD64/Ulip/CRMP).8 Five vertebrate CRMP genes (CRMP1-5) have been identified, while the genome appears to encode for only a single CRMP. CRMP1-4 share ~75% protein sequence identity with each other, however CRMP5 (also referred to as CRAM) is only 50C51% homologous. CRMPs talk about a high series homology using the gene,5,7,9,10 although two various other nematode genes, CeCRMP1 and 2, have already been categorized in the CRMP family members.11 In addition, mammalian CRMP1, 2, and 4 appear to undergo alternative splicing.12,13 CRMP isoforms strongly interact with each other and exist as heterotetramers when purified from brain.14 Specificity exists for the hetero-oligomerization in that different isoforms have varying affinities for each other.14 Information obtained from the examination of the crystal structure of CRMP1 homotetramers reveals that this specificity is likely due to differential polar and hydrophobic residues between isoforms at the two oligomerization interfaces.15 CRMP1-4 genes share a high sequence homology (60%) with the liver dihydropyrimidinase (DHPase) and structural similarity with members of the metal-dependent amidohydrolases, both of which form stable tetramers. However, none of the CRMP isoforms demonstrate any enzymatic activity, likely due to the fact that they lack crucial His residues which coordinate binding of a metal atom at the active site of amidohydrolase enzymes.6,14,15 CRMPs were discovered to be one of the first proteins expressed in newly born neurons in the developing brain,5 and CRMP2 expression has CHR2797 cost been shown to be induced by factors that promote neuronal differentiation such as noggin, chordin, GDNF, and FGF.16C18 Not surprisingly, CRMPs are most highly expressed during the neurogenic period of brain development and expression peaks during the period of axon growth.19 In addition, CRMP1, 2 and 5 are expressed in immature CHR2797 cost interneurons in the adult olfactory bulb,20 a site of ongoing neurogenesis in adulthood.21 The expression of CRMPs is restricted primarily to the nervous system, however some isoforms show a differential pattern of expression in various nervous system structures.19,22 CRMP2, and to some extent CRMP3, are expressed in mature neurons at low levels. These expression patterns, when taken together with the fact that CRMPs form heterotetramers, imply that oligomers consisting of different combinations of monomeric isoforms may have different functional effects in various cell types. The significant sequence similarity of CRMPs with the worm gene implies a role for CRMP in axon growth and morphology, since mutants display severe axonal abnormalities.23,24 Also, overexpression of CRMP2 induces ectopic axon formation in cultured hippocampal cells.25 Although CRMP is a CHR2797 cost cytosolic protein, a significant fraction has been shown CHR2797 cost to be tightly associated with the cell membrane.5,26 hSPRY2 This membrane-associated pool of CRMP is enriched at the leading edge of the growth cone lamellipodium and filopodia, further supporting a role in axon outgrowth and guidance.5 All CRMP isoforms continue to be expressed through the period of axon.