Intermediate filaments in peripheral nervous system: Their expression, dysfunction and diseases.

Characteristics of the intermediate filament proteins (IFPs) expressed during the development and cell differentiation of peripheral neurons are here reviewed. Neurofilament triplet proteins (NFPs), peripherin, α-internexin, synemin, syncoilin, nestin, vimentin and glial fibrillary acidic protein (GFAP) are each produced by different genes. NFPs, the most extensively studied, are thought to maintain axonal caliber, thus ensuring normal axonal transport, but this network is highly disrupted in several diseases, particularly motor neuron diseases. α-internexin has been proposed as the fourth NFP subunit. The relative plasticity of the peripherin network may account for its possible role during development, when axons have to find their targets, and when axons regenerate. In addition to their expression in muscle, other IFPs, such as syncoilin and synemin, are also expressed in neuronal tissues. Syncoilin modulates peripherin filament networks. Synemin M, associated with peripherin, is present in small unmyelinated fibers, whereas synemin L is produced in large neurons with myelinated fibers positive for the light-chain neurofilament (NF-L) subunit. Nestin is an IFP expressed in dividing cells during early stages of development in the central and peripheral nervous systems, and in muscles and other tissues. After differentiation, nestin is downregulated and replaced by tissue-specific IFPs. IFPs in glial cells are primarily composed of GFAP, although vimentin is also expressed; vimentin is also widely distributed in mesenchymal derivatives and established cell lines. In the peripheral nervous system, NFPs appear early in its development and progressively replace vimentin, which is expressed before NFPs in most, if not all, dividing neuroepithelial cells. In addition, in tissues undergoing an injury response, the unique and complex cell and tissue distribution of IFPs can be markedly modified.

Synemin isoforms in astroglial and neuronal cells from human central nervous system.

The intermediate filament (IF) synemin gene encodes three IF proteins (H 180, M 150, L 41 kDa) with overlapping distributions. Synemin M was present early with vimentin and nestin. Synemin H was found later in the nervous system and mesodermic derivatives concomitantly with angiogenesis and the migration of neural crest cells. Synemin L appeared later in neurons. A series of in vitro cell cultures were done to identify the linkage between synemin isoforms and specific cell types of the central nervous system (CNS). The neurons and glia from the brains of humans and rats were cultured and double immunostaining done with antibodies against the H/M or L synemin isoforms and neural cell types (betaIII-tubulin or NeuN) or astrocyte intermediate filaments (GFAP or vimentin). In neurons of the CNS, synemin H/M were co-expressed with GFAP, vimentin or nestin in glial cells, whereas synemin L was found in neurons.

Different expression of synemin isoforms in glia and neurons during nervous system development.

The synemin gene encodes proteins belonging to the intermediate filament family. These proteins confer resistance to mechanical stress and modulate cell shape. Three synemin isoforms, of 180 (H), 150 (M) and 41 (L) kDa, are produced by alternative splicing of the pre-mRNA and are regulated differently during development. The three isoforms differ in their C-terminal tail domains, while their IF rod domains are identical. Synemins H/M occurred together with nestin and vimentin in glial progenitors during the early differentiation of the developing mouse central nervous system. They are later found in GFAP-labeled cells. In contrast, the L isoform appeared only in neurons, together with neurofilaments and betaIII-tubulin in the brain after birth. However, synemin L appeared from E13 in the peripheral nervous system, where it was confined to the neurons of spinal ganglia. In the meantime, the synemin H/M isoforms were found in both the neurons and Schwann cells of the sensorial ganglia from E11. Tissue fractionation and purification of IFs from adult mouse spinal cord revealed that the synemin L isoform binds to neurofilaments associated with the membrane compartment. This report describes the synthesis of the three synemin isoforms by selective cell types, and their temporal and spatial distributions. Mechanisms specific to neurons and glia probably control the splicing of the common synemin mRNA and the synthesis of each synemin isoform.

The mouse synemin gene encodes three intermediate filament proteins generated by alternative exon usage and different open reading frames.

We have previously cloned and characterized the human synemin gene, which encodes two intermediate filament proteins (IFPs). We now show that the mouse synemin gene encodes three different synemin isoforms through an alternative splicing mechanism. Two of them, synemin H and M are similar to human alpha and beta synemin, and the third isoform, L synemin, constitutes a new form of IFP. It has a typical rod domain and a short tail (49 residues) with a novel sequence that is produced by a different open reading frame. The synthesis of H/M synemins starts in the embryo, whereas the synemin L isoform is present in adult muscles. The H/M isoforms are bound to desmin or vimentin in the muscle cells of wild-type mice. Using desmin- and vimentin-deficient mice, we have obtained direct evidence that synemin is associated with muscle intermediate filaments in vivo. The organization of the synemin fibril is disrupted in skeletal and cardiac muscle when desmin is absent and in smooth muscle when vimentin is absent. The fact that the three synemin isoforms differ in the sequences of their tail domains as well as in their developmental patterns suggests that they fulfill different functions.