An Essential Cytoskeletal Linker Protein Connecting Actin Microfilaments to Intermediate Filaments

Abstract

Typified by rapid degeneration of sensory neurons, dystonia musculorum mice have a defective BPAG1 gene, known to be expressed in epidermis. We report a neuronal splice form, BPAG1n, which localizes to sensory axons. Both isoforms have a coiled-coil rod, followed by a carboxy domain that associates with intermediate filaments. However, the amino terminus of BPAG1n differs from BPAG1e in that it contains a functional actin-binding domain. In transfected cells, BPAG1n coaligns neurofilaments and microfilaments, establishing this as a cytoskeletal protein interconnecting actin and intermediate filament cytoskeletons. In BPAG1 null mice, axonal architecture is markedly perturbed, consistent with a failure to tether neurofilaments to the actin cytoskeleton and underscoring the physiological relevance of this protein.

Dystonin/Bpag1—A link to what?

“…Also, incomplete and sometimes erroneous descriptions of the Dst gene ( Fig. 1) have lead to conflicting reports regarding the function and nature of dystonin proteins [Yang et al, 1996;Dalpé et al, 1999;Leung et al, 1999].…”

“…While loss of Bpag1 function results in minor skin abnormalities in mice, it was clear that it is the loss of function of an essential isoform (or isoforms) unique to the neuromuscular system that causes the neurodegenerative condition in dt mice. It was during this time that the putative Bpag1n1, n2, and n3 neuronal isoforms were described Yang et al, 1996Yang et al, , 1999.…”

“…The Dst gene was initially thought to encode only the originally described epithelial isoform, with the neuronal variants (n1, n2, and n3) having the N-terminal ABD and alternate N-terminal regions Yang et al, 1996Yang et al, , 1999. Subsequently, conflicting data from Leung et al [2001] questioned the existence of the n1, n2, and n3 neuronal variants.…”

Dynamics and unexpected localization of the plakin binding protein, kazrin, in mouse eggs and early embryos

“…Seven plakin family members have been identified. They all share the ability to link cytoskeletal filaments to an intercellular junction complex, whereas a few members recently have been shown to link intermediate filaments to actin and tubulin (Yang et al, 1996(Yang et al, , 1999Karakesisoglou et al, 2000;Weber and Bement, 2002).…”

“…As a result, the cell has assembled an abundant array of transcriptional, translational, and posttranslational mechanisms to carefully control cytoskeletal morphology and function. One of the more recent findings encompassing cytoskeletal regulation has been the discovery of crosslinker proteins that act by crosslinking cytoskeletal filament systems (i.e., actin, microtubules, and intermediate filaments), linking cytoskeletal filament systems to intercellular junctions (i.e., adherens junctions, desmosomes, gap junctions, and tight junctions), and linking different types of cellular junctions to each other (Sobel, 1990;Yang et al, 1996Yang et al, , 1999Karakesisoglou et al, 2000;Leung et al, 2002;Weber and Bement, 2002;Giepmans, 2004;Jang et al, 2005;Winder and Ayscough, 2005).…”