Primary cilia are evolutionary conserved cell organelles involved in sensing of extracellular signals during development and adulthood. Signaling pathways mediated by primary cilia comprise sonic hedgehog (SHH) signaling, transforming growth factor (TGF)-ß signaling, G protein-coupled receptor (GPCR) signaling, platelet-derived growth factor receptor (PDGFR)-a, mechanistic target of rapamycin (mTOR) signaling, Hippo signaling, Notch signaling, Wnt signaling and many more. Primary cilia consist of a nine-duplet microtubular filament ring that arises from the mother centriole and is covered by the ciliary membrane. Recent studies also demonstrate an interplay between primary cilia and the regulation of proteostasis, e.g. the induction and activity control of autophagy and the ubiquitin- proteasome system. Additionally, it has been shown that the primary cilium functions as a signaling hub to control energy homeostasis. For instance, ciliary proteins take part in hypothalamic neuron signaling and adipocyte differentiation. The relationships between primary cilia and proteostasis as well as between primary cilia and energy homeostasis are emerging fields and mechanisms that mediate primary cilia or basal body derived signals to modulate cellular energy homeostasis and proteostasis are largely unknown.
Primary cilia dysfunction plays a significant role in hereditary organ-specific or syndromic diseases summarized as ciliopathies, such as Leber’s congenital amaurosis, polycystic kidney disease, nephronophthisis, primary ciliary dyskinesia, Meckel-Gruber syndrome, Joubert syndrome, Bardet-Biedl syndrome, Alström syndrome, Senior-Løken syndrome, otopalatodigital syndrome, orofaciodigital syndrome, Jeune asphyxiating thoracic dystrophy, Ellis–van Creveld syndrome, Sensenbrenner syndrome (cranioectodermal dysplasia) and others. The clinical picture ranges from isolated organ manifestations, e.g. restriction to the eye in Leber’s congenital amaurosis, to syndromic and severe diseases, such as the Meckel-Gruber syndrome which is characterized by defects in the central nervous system (most frequently occipital encephalocele), postaxial polydactyly, cystic kidneys, cystic liver, ductal proliferation in the portal area of the liver, eye defects (e.g. microphthalmia), orofacial clefts and heart abnormalities. To this end, it is unclear to what extent the molecular mechanisms underlying ciliopathies include impaired cilia-regulated proteostasis and/or cilia-controlled energy homeostasis.
This research topic is planned to bring together expertise from the field to get an overview of the different cilia-mediated signal transduction pathways that are involved in the regulation of proteostasis and energy homeostasis. In this way, the research topic contributes to the important endeavor to provide novel insights into the molecular mechanisms underlying ciliopathies to develop novel treatment strategies.
Primary cilia are evolutionary conserved cell organelles involved in sensing of extracellular signals during development and adulthood. Signaling pathways mediated by primary cilia comprise sonic hedgehog (SHH) signaling, transforming growth factor (TGF)-ß signaling, G protein-coupled receptor (GPCR) signaling, platelet-derived growth factor receptor (PDGFR)-a, mechanistic target of rapamycin (mTOR) signaling, Hippo signaling, Notch signaling, Wnt signaling and many more. Primary cilia consist of a nine-duplet microtubular filament ring that arises from the mother centriole and is covered by the ciliary membrane. Recent studies also demonstrate an interplay between primary cilia and the regulation of proteostasis, e.g. the induction and activity control of autophagy and the ubiquitin- proteasome system. Additionally, it has been shown that the primary cilium functions as a signaling hub to control energy homeostasis. For instance, ciliary proteins take part in hypothalamic neuron signaling and adipocyte differentiation. The relationships between primary cilia and proteostasis as well as between primary cilia and energy homeostasis are emerging fields and mechanisms that mediate primary cilia or basal body derived signals to modulate cellular energy homeostasis and proteostasis are largely unknown.
Primary cilia dysfunction plays a significant role in hereditary organ-specific or syndromic diseases summarized as ciliopathies, such as Leber’s congenital amaurosis, polycystic kidney disease, nephronophthisis, primary ciliary dyskinesia, Meckel-Gruber syndrome, Joubert syndrome, Bardet-Biedl syndrome, Alström syndrome, Senior-Løken syndrome, otopalatodigital syndrome, orofaciodigital syndrome, Jeune asphyxiating thoracic dystrophy, Ellis–van Creveld syndrome, Sensenbrenner syndrome (cranioectodermal dysplasia) and others. The clinical picture ranges from isolated organ manifestations, e.g. restriction to the eye in Leber’s congenital amaurosis, to syndromic and severe diseases, such as the Meckel-Gruber syndrome which is characterized by defects in the central nervous system (most frequently occipital encephalocele), postaxial polydactyly, cystic kidneys, cystic liver, ductal proliferation in the portal area of the liver, eye defects (e.g. microphthalmia), orofacial clefts and heart abnormalities. To this end, it is unclear to what extent the molecular mechanisms underlying ciliopathies include impaired cilia-regulated proteostasis and/or cilia-controlled energy homeostasis.
This research topic is planned to bring together expertise from the field to get an overview of the different cilia-mediated signal transduction pathways that are involved in the regulation of proteostasis and energy homeostasis. In this way, the research topic contributes to the important endeavor to provide novel insights into the molecular mechanisms underlying ciliopathies to develop novel treatment strategies.
