Showing papers by "Wen Cheng Xiong published in 2006"

Regulation of osteoclast function and bone mass by RAGE

Abstract: The receptor for advanced glycation end products (RAGE) is a member of the immunoglobulin superfamily that has multiple ligands and is implicated in the pathogenesis of various diseases, including diabetic complications, neurodegenerative disorders, and inflammatory responses. However, the role of RAGE in normal physiology is largely undefined. Here, we present evidence for a role of RAGE in osteoclast maturation and function, which has consequences for bone remodeling. Mice lacking RAGE had increased bone mass and bone mineral density and decreased bone resorptive activity in vivo. In vitro–differentiated RAGE-deficient osteoclasts exhibited disrupted actin ring and sealing zone structures, impaired maturation, and reduced bone resorptive activity. Impaired signaling downstream of αvβ3 integrin was observed in RAGE−/− bone marrow macrophages and precursors of OCs. These results demonstrate a role for RAGE in osteoclast actin cytoskeletal reorganization, adhesion, and function, and suggest that the osteosclerotic-like phenotype observed in RAGE knockout mice is due to a defect in osteoclast function.

Lipid Rafts Serve as a Signaling Platform for Nicotinic Acetylcholine Receptor Clustering

Abstract: Agrin, a motoneuron-derived factor, and the muscle-specific receptor tyrosine kinase (MuSK) are essential for the acetylcholine receptor (AChR) clustering at the postjunctional membrane. However, the underlying signaling mechanisms remain poorly defined. We show that agrin stimulates a dynamic translocation of the AChR into lipid rafts-cholesterol and sphingolipid-rich microdomains in the plasma membrane. This follows MuSK partition into lipid rafts and requires its activation. Disruption of lipid rafts inhibits MuSK activation and downstream signaling and AChR clustering in response to agrin. Rapsyn, an intracellular protein necessary for AChR clustering, is located constitutively in lipid rafts, but its interaction with the AChR is inhibited when lipid rafts are perturbed. These results reveal that lipid rafts may regulate AChR clustering by facilitating the agrin/MuSK signaling and the interaction between the receptor and rapsyn, both necessary for AChR clustering and maintenance. These results provide insight into mechanisms of AChR cluster formation.

Shp2 is dispensable in the formation and maintenance of the neuromuscular junction.

Abstract: SHP2, a protein tyrosine phosphatase with two SH2 domains, has been implicated in regulating acetylcholine receptor (AChR) gene expression and cluster formation in cultured muscle cells To understand the role of SHP2 in neuromuscular junction (NMJ) formation in vivo, we generated mus cle-specific deficient mice by using a loxP/Cre strategy since Shp2 null mutation causes embryonic lethality Shp2(floxed/floxed) mice were crossed with mice expressing the Cre gene under the control of the human skeletal alpha-actin (HSA) promoter Expression of SHP2 was reduced or diminished specifically in skeletal muscles of the conditional knockout (CKO) mice The mutant mice were viable and fertile, without apparent muscle defects The mRNA of the AChR alpha subunit and AChR clusters in CKO mice were localized in a narrow central region surrounding the phrenic nerve primary branches, without apparent change in intensity AChR clusters colocalized with markers of synaptic vesicles and Schwann cells, suggesting proper differentiation of presynaptic terminals and Schwann cells In comparison with age-matched littermates, no apparent difference was observed in the size and length of AChR clusters in CKO mice Both the frequency and amplitude of mEPPs in CKO mice were similar to those in controls, suggesting normal neurotransmission when SHP2 was deficient These results suggest that Shp2 is not required for NMJ formation and/or maintenance

The role of the cytoskeleton in neuromuscular junction formation.

Abstract: The cytoskeleton plays a vital role in neuromuscular junction (NMJ) formation. It is responsible for shaping synaptic membrane into folds opposed to presynaptic active zones and anchoring acetylcholine receptors (AChRs) to the crest of the junctional folds. Acetylcholine receptors (AChRs) associate with the actin cytoskeleton, the disruption of which affects spontaneous and agrin-induced AChR clusters (Prives et al., 1982; Connolly, 1984; Peng and Phelan, 1984; Bloch, 1986; Dai et al., 2000). How AChRs are tethered to the actin cytoskeleton remains unclear.

Mitochondrial amyloid-beta peptide: Pathogenesis or late-phase development?

Abstract: Mitochondrial and metabolic dysfunction have been linked to Alzheimer's disease for some time Key questions regarding this association concern the nature and mechanisms of mitochondrial dysfunction, and whether such changes in metabolic properties are pathogenic or secondary, with respect to neuronal degeneration In terms of mitochondria and Alzheimer's, altered function could reflect intrinsic properties of this organelle, potentially due to mutations in mitochondrial DNA, or extrinsic changes secondary to signal transduction mechanisms activated in the cytosol This review presents data relevant to these questions, and considers the implication of recent findings demonstrating the presence of amyloid-beta peptide in mitochondria, as well as intra-mitochondrial molecular targets with which it can interact Regardless of the underlying mechanism(s), it is likely that mitochondrial dysfunction contributes to oxidant stress which is commonly observed in brains of patients with Alzheimer's and transgenic models of Alzheimer's-like pathology

MuSK signaling at the neuromuscular junction.

Abstract: The neuromuscular junction (NMJ) is a peripheral cholinergic synapse that conveys signals from motor neurons to muscle cells (Sanes and Lichtman, 1999; Sanes and Lichtman, 2001). The formation of the NMJ requires communication between motoneurons and muscle fibers. Three molecules are essential for NMJ formation: agrin, MuSK, and rapsyn. MuSK appears to be involved in every aspect of NMJ development and maintenance. The paper reviews agrin-MuSK cascades and its potential cross talk with Wnt signaling pathways.