The analysis of Cav1α function in Xenopus motoneuron outgrowth and neuromuscular integrity
Caveolin 1 (Cav1) is a versatile membrane protein that plays a role in the pathogenesis of hereditary lipodystrophy and neurodegenerative diseases such as Alzheimer. As an essential structural component of caveolae, specialized membrane invaginations, it participates in a broad spectrum of cellular...
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|Summary:||Caveolin 1 (Cav1) is a versatile membrane protein that plays a role in the pathogenesis of hereditary lipodystrophy and neurodegenerative diseases such as Alzheimer. As an essential structural component of caveolae, specialized membrane invaginations, it participates in a broad spectrum of cellular processes, including the regulation of lipid homeostasis, endocytosis as well as cell signaling by acting as adapter molecule for a diverse number of signaling molecules, including small RhoGTPases. The loss of Cav1 function in mice causes distinct neurological abnormalities, including deficits in motor coordination and strength, behavioural changes as well as progressive neurodegeneration. However, the contribution of Cav1 to this phenotype is currently under investigation. Here, Xenopus laevis was used as model organism to study the developmental relevance of Cav1α with the main focus on the neuromuscular system. Morpholino oligonucleotide (MO) mediated knockdown of Cav1α results in a striking swimming defect, which is characterized by the paralysis of the injected side in combination with a severely disrupted sarcomeric organization of the somitic muscle cells. Expression analysis of Cav1 revealed a prominent expression in motoneurons, but not in the musculature indicating that Cav1 functions in the neuromuscular system. This could be confirmed by targeted injection of the Cav1α MO into neural tissue, which disrupted swimming behaviour as well as axonal growth of motoneuron. In contrast, targeted injection of Cav1 into muscular tissue had no effect on the swimming behaviour. In addition, neuronal explants revealed a striking increase in both lamellipodia as well as filopodia formation in the Cav1α morphant axons. By performing rescue experiments, it could be demonstrated that Cav1 regulates the activity of the small RhoGTPases Cdc42, Rac1 as well as RhoA during axonal growth. Further, phosphorylation on tyrosine 14 of the Cav1α protein likely modulates this process, as a phosphorylation-null mutant was not able to rescue the morphant swimming phenotype. Taken together, this thesis demonstrated a previously unrecognized function of Cav1α in the neuromuscular system, by regulating the activity of the small RhoGTPases RhoA, Rac1 and Cdc42, thereby affecting the dynamic of the actin cytoskeleton.|
|Physical Description:||170 Pages|