Integrators of the Cytoskeleton that Stabilize Microtubules

Abstract

Sensory neurodegeneration occurs in mice defective in BPAG1, a gene encoding cytoskeletal linker proteins capable of anchoring neuronal intermediate filaments to actin cytoskeleton. While BPAG1 null mice fail to anchor neurofilaments (NFs), BPAG1/NF null mice still degenerate in the absence of NFs. We report a novel neural splice form that lacks the actin-binding domain and instead binds and stabilizes microtubules. This interaction is functionally important; in mice and in vitro, neurons lacking BPAG1 display short, disorganized, and unstable microtubules defective in axonal transport. Ironically, BPAG1 neural isoforms represent microtubule-associated proteins that when absent lead to devastating consequences. Moreover, BPAG1 can functionally account for the extraordinary stability of axonal microtubules necessary for transport over long distances. Its isoforms interconnect all three cytoskeletal networks, a feature apparently central to neuronal survival.

Dystonin/Bpag1—A link to what?

“…Much of the isoform 2-specific sequence was originally identified in Brown et al [1995a], though the start site was not identified (indicated by an X). The original isoform 3-specific sequence was largely incomplete and erroneous due to an apparent sequencing error [Yang et al, 1999] indicated by an X.…”

“…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).…”