Ciliary and non-ciliary functions of Bardet-Biedl syndrome proteins
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Abstract
Primary cilia are microtubule-based cell organelles that are required for the communication between cells in a tissue and the regulation of intracellular signalling pathways. They are important for tissue development and homeostasis, which is why defects in primary cilia are often associated with genetic disorders, collectively termed ciliopathies. Bardet-Biedl syndrome (BBS) as a flagship ciliopathy combines many clinical features such as retinopathies, kidney disease, obesity and polydactyly. Responsible for the occurrence of BBS are mutations in BBS genes, encoding proteins that are required for primary cilia development, maintenance and function. Although the ciliary function of BBS proteins has been largely discussed, recent research also suggests non-ciliary functions of BBS proteins, indicating more complex mechanisms being involved in the development of human ciliopathies. The knowledge of these complex processes is inevitable to understand ciliopathies in a broader context, enabling a better diagnosis and the potential for development of therapeutics that target these pathways. In the current thesis, the ciliary and non-ciliary functions of BBS proteins were investigated in more detail, demonstrating complex tissue-dependent mechanisms that shed light on the signalling networks of BBS proteins on a cellular level. Publication I suggested that the function of BBS proteins could possibly be tissue-dependent, indicating previously unidentified regulations in specific tissues that need to be examined in more detail. While analysing the ciliarelated function of BBS proteins more closely in Publication II, the BBS proteins BBS6 and BBS8 were found to cooperate with the Wnt signalling protein Inversin in regulating Wnt signalling and ciliary disassembly pathways. These data shed light on how BBS proteins regulate ciliogenesis in addition to their classical defined ciliary function and elucidate their role in Wnt signalling. Since Wnt signalling affects the downstream actin network, the implication on important actin-based structures such as filopodia was investigated in more detail in Manuscript I. These data showed that BBS6 affects filopodia via interaction with the actin regulator Fascin-1. Contrary, Fascin-1 localises to primary cilia and its loss provoked a ciliary phenotype, indicating a feedback regulation of Fascin-1 and actin in ciliogenesis. The ciliary phenotype further led to alterations of Wnt signalling, enlightening how actin proteins affect ciliogenesis and cilia-related signalling. In summary, this thesis demonstrates how ciliary BBS proteins affect ciliogenesis and cilia related Wnt signalling potentially in a tissue-dependent manner and provide a better understanding in how cilia, Wnt and actin regulators affect each other in complex feedback mechanisms. These data provide a basis for studying cilia-related and unrelated functions of BBS proteins in the context of different tissues. They further emphasise the tight connection between ciliogenesis and actin proteins that should be considered in future studies to understand the complex molecular background of human ciliopathies.