CELLULAR TRANSGLUTAMINASES IN NEURAL DEVELOPMENT

Enzymes of the transglutaminase family catalyze the Ca2+-dependent covalent cross-linking of peptide-bound glutamine residues of proteins and glycoproteins to the epsilon-amino group of lysine residues to create inter- or intramolecular isopeptide bonds. Transglutaminases can also covalently link a variety of primary amines to peptide-bound glutamine residues giving rise to two possibilities; firstly, where the primary amine has two or more amine groups, further catalysis can result in the formation of cross-linked bridges between glutamine residues, and secondly, where the primary amine is a monoamine, glutamine residues are rendered inert to further modification. The products are therefore in the main, homo-or heterodimers, or extensive, metabolically-stable multimeric complexes or matrices. Ca2+-dependent transglutaminase activity is present in the mammalian peripheral and central nervous systems and transglutaminase-catalyzed cross-linking of endogenous substrates has been demonstrated in neurons of Aplysia and the mammalian brain. Transglutaminase activity increases in the brain during development, principally owing to the increasing preponderance of glial cell activity. In a few regions including the cerebellar cortex, activity is also high in early development. Cellular transglutaminases occur widely in differentiating cells and tissues in mammals, with more than one transglutaminase frequently associated with a single cell type. The primary protein sequences of three cellular transglutaminases have been fully determined in different species, together with that of a mammalian protein homologue (band 4.2) which shares extensive sequence homologies with transglutaminases, but lacks the active site cysteine residue. The upstream sequences of two mammalian cellular transglutaminase genes (C and K) contain numerous regulatory sites, and an invertebrate transglutaminase, annulin, is spatially regulated within homeodomains. Multiple molecular forms of transglutaminase C and possibly other cellular transglutaminases exist in mammalian brain. The emerging picture is one of a family of cytosolic and membrane-bound proteins central to several regulatory pathways whose functions is to stabilize the cellular and intercellular superstructure in growing organisms. The targeted formation of glu-lys isopeptide bonds between proteins is central to this function. Cytoskeletal proteins, membrane-associated receptors, enzymes in signal transduction pathways and extracellular glycoproteins are candidate substrates as are polyamines, but few cellular proteins have been identified as components of naturally-occurring covalently-bonded matrices. Transglutaminases participate in the programme of neuronal differentiation in some but not all classes of neurone. Both neuronal and non-neuronal expression of transglutaminases may be important for guidance of migrating neurons or growth cones and sustainment of cell shape and coordinates during development. Cross-linking reactions may induce receptor clustering and amplify signalling pathways. Finally, in some forms of programmed cell death, expression of high levels of transglutaminase may play a part in cytological degeneration and apoptosis.