Role of lipids in the control of autophagy and primary cilium signaling in neurons

The brain is,after the adipose tissue,the organ with the greatest amount of lipids and diversity in their composition in the human body.In neurons,lipids are involved in signaling pathways controlling autophagy,a lysosome-dependent catabolic process essential for the maintenance of neuronal homeostasis and the function of the primary cilium,a cellular antenna that acts as a communication hub that transfers extracellular signals into intracellular responses required for neurogenesis and brain development.A crosstalk between primary cilia and autophagy has been established;however,its role in the control of neuronal activity and homeostasis is barely known.In this review,we briefly discuss the current knowledge regarding the role of autophagy and the primary cilium in neurons.Then we review the recent literature about specific lipid subclasses in the regulation of autophagy,in the control of primary cilium structure and its dependent cellular signaling in physiological and pathological conditions,specifically focusing on neurons,an area of research that could have major implications in neurodevelopment,energy homeostasis,and neurodegeneration.

Control of the Hedgehog pathway by compartmentalized PKA in the primary cilium

The Hedgehog(Hh)signaling is one of the essential signaling pathways during embryogenesis and in adults.Hh signal transduction relies on primary cilium,a specialized cell surface organelle viewed as the hub of cell signaling.Protein kinase A(PKA)has been recognized as a potent negative regulator of the Hh pathway,raising the question of how such a ubiquitous kinase specifically regulates one signaling pathway.We reviewed recent genetic,molecular and biochemical studies that have advanced our mechanistic understanding of PKA’s role in Hh signaling in vertebrates,focusing on the compartmentalized PKA at the centrosome and in the primary cilium.We outlined the recently developed genetic and optical tools that can be harvested to study PKA activities during the course of Hh signal transduction.

Ciliotherapy： a novel intervention in polycystic kidney disease

Background Ciliopathies are a group of diseases associated with abnormal structure or function of primary cilia. Ciliopathies include polycystic kidney disease （PKD）, a pathology associated with vascular hypertension. We previously showed that cilia length regulates cilia function, and cilia function is required for nitric oxide （NO） biosynthesis in endothelial cells. Because patients with PKD show abnormal sensory cilia function, the aim of our current study was to search for a targeted therapy focused on primary cilia, which we refer to as ＇cilio- therapy＇. Methods and Results In the present studies, our in vitro analyses refined fenoldopam as an equipotent and more specific dopa- minergic agonist to regulate cilia length and function. Our in vivo studies indicated that fenoldopam increased cilia length and serum NO thereby reducing blood pressure in a PKD mouse model. Our crossover, multicenter, double-blind and placebo-controlled clinical study further indicated that cilia-targeting therapy showed an overall reduction in mean arterial pressure in PKD patients. Conclusions Overall, our studies provide the first evidence of ciliotherapy as an innovative intervention in patients with abnormal primary cilia.

Stem cells' centrosomes: How can organelles identified 130 years ago contribute to the future of regenerative medicine?

At the core of regenerative medicine lies the expectation of repair or replacementof damaged tissues or whole organs. Donor scarcity and transplant rejection aremajor obstacles, and exactly the obstacles that stem cell􀀀based therapy promisesto overcome. These therapies demand a comprehensive understanding of theasymmetric division of stem cells, i.e. their ability to produce cells with identicalpotency or differentiated cells. It is believed that with better understanding,researchers will be able to direct stem cell differentiation. Here, we describeextraordinary advances in manipulating stem cell fate that show that we need tofocus on the centrosome and the centrosome-derived primary cilium. This beliefcomes from the fact that this organelle is the vehicle that coordinates theasymmetric division of stem cells. This is supported by studies that report thesignificant role of the centrosome/cilium in orchestrating signaling pathways thatdictate stem cell fate. We anticipate that there is sufficient evidence to place thisorganelle at the center of efforts that will shape the future of regenerativemedicine.

Potential Application of TCM Sophoridine in Regulating Intensity of Autophagy to Treat PKD

Nearly all cells have primary cilia( PC) composed of microtubules,primary cilia mainly functioning as sensing various signals of the environment and coordinating intracellular signaling pathways. Autophagy is an adaptive response of cells to environmental stress such as starvation/inflammation and infection. Many ciliopathies may induce autophagy. Polycystic kidney disease( PKD) is the most common ciliopathy,with the incidence of 1/500 to 1/1 000 in the world. A typical symptom of the PKD is the chronic development of multiple renal cysts that may eventually develop into advanced kidney disease. Sophoridine is an alkaloid extracted from the traditional Chinese medicinal plant Sophora alopecuroides L. It is a new antitumor drug which has the function of inducing cell autophagy. This paper mainly discussed the possibility of treating PKD through sophoridine inducing autophagy.

Mechanosensation of osteocyte with collagen hillocks and primary cilia under pressure and electric field stimulation

Mechanosensors are the most important organelles for osteocytes to perceive the changes of surrounding mechanical environment.To evaluate the biomechanical effectiveness of collagen hillock,cell process and primary·cilium in lacunar-canalicular system(LCS),we developed pressure-electricity-structure interaction models by using the COMSOL Multiphysics software to characterize the deformation of collagen hillocks-and primary cilium-based mechanosensors in osteocyte under fluid flow and electric field stimulation.And mechanical signals(pore pressure,fluid velocity,stress,deformation)were analyzed in LCS.The effects of changes in the elastic modulus of collagen hillocks,the number and location of cell processes,the length and location of primary cilia on the mechanosensitivity and the overall poroelastic responses of osteocytes were studied.These models predict that the presence of primary cilium and collagen hillocks resulted in significant stress amplifications(one and two orders of magnitude larger than osteocyte body)on the osteocyte.The growth of cell process along the long axis could stimulate osteocyte to a higher level than along the short axis.The Mises stress of the basal body of primary cilia near the top of osteocyte is 8 Pa greater than that near the bottom.However,the presence of collagen hillocks and primary cilium does not affect the mechanical signal of the whole osteocyte body.The established model can be used for studying the mechanism of bone mechanotransduction at the multiscale level.

The roles and activation of endocardial Notch signaling in heart regeneration

As a highly conserved signaling pathway in metazoans,the Notch pathway plays important roles in embryonic development and tissue regeneration.Recently,cardiac injury and regeneration have become an increasingly popular topic for biomedical research,and Notch signaling has been shown to exert crucial functions during heart regeneration as well.In this review,we briefly summarize the molecular functions of the endocardial Notch pathway in several cardiac injury and stress models.Although there is an increase in appreciating the importance of endocardial Notch signaling in heart regeneration,the mechanism of its activation is not fully understood.This review highlights recent findings on the activation of the endocardial Notch pathway by hemodynamic blood flow change in larval zebrafish ventricle after partial ablation,a process involving primary cilia,mechanosensitive ion channel Trpv4 and mechanosensitive transcription factor Klf2.