The primary cilium is an antenna-like structure that protrudes from the cell surface of quiescent/differentiated cells and participates in extracellular signal processing [1][2][3] . Here, we report that mice deficient for the lipid 5-phosphatase Inpp5e develop a multiorgan disorder associated with structural defects of the primary cilium. In ciliated mouse embryonic fibroblasts, Inpp5e is concentrated in the axoneme of the primary cilium. Inpp5e inactivation did not impair ciliary assembly but altered the stability of pre-established cilia after serum addition. Blocking phosphoinositide 3-kinase (PI3K) activity or ciliary platelet-derived growth factor receptor a (PDGFRa) restored ciliary stability. In human INPP5E, we identified a mutation affecting INPP5E ciliary localization and cilium stability in a family with MORM syndrome, a condition related to Bardet-Biedl syndrome. Together, our results show that INPP5E plays an essential role in the primary cilium by controlling ciliary growth factor and PI3K signaling and stability, and highlight the consequences of INPP5E dysfunction.Lipid 5-phosphatases selectively remove the phosphate from position D-5 of the inositol ring of phosphoinositides and inositolphosphates 4,5 . To characterize the functions of the 5-phosphatase Inpp5e 6-8 , we generated Inpp5e D/+ mice ( Supplementary Fig. 1a). We obtained no adult Inpp5e D/D mutant mice from intercrosses between Inpp5e D/+ mice. However, at embryonic day 13.5 (E13.5) and E18.5, 16.9% (11/65) and 14.8% (12/81) of embryos were homozygous for the deletion allele, respectively. The mutant mice died soon after birth, indicating that total inactivation of Inpp5e led to embryonic and postnatal death. Analyses confirmed the absence of Inpp5e protein in mutant cells and tissues (Fig. 1a). Inpp5e D/D mice presented with bilateral anophthalmos (100%, n ¼ 43) and postaxial hexadactyly (62.5%, n ¼ 16; Fig. 1b,c). Histological analyses revealed that eye development ceased at the optic vesicle stage, just before the appearance of the optic cup (Fig. 1d). Analysis of kidneys from the mice revealed the presence of multiple cysts (100%, n ¼ 10; Fig. 1e). Of the cysts, 84% expressed AQP2 and 14% expressed AQP1, indicating an origin in cortical collecting and connecting ducts (when AQP2 + ) as well as proximal tubules and the descending limb of the loop of Henle (when AQP1 + ) ( Supplementary Fig. 2). Only 2% of the renal glomeruli were cystic. Inpp5e D/D embryos had skeletal abnormalities such as a bifid sternum (50%, n ¼ 6), delayed ossification of metacarpals and phalanges (100%, n ¼ 5) and cleft palate (75%, n ¼ 4; Fig. 1f-h). We identified cerebral developmental defects, such as anencephaly and exencephaly, in 30% of Inpp5e D/D embryos at E15.5 (n ¼ 30; Fig. 1i,j). We did not detect liver alterations, laterality defects or respiratory cilium defects in mutant animals. The tissue localization of lesions observed in Inpp5e D/D embryos matched the tissue expression of Inpp5e mRNA during mouse embryogenesis ( Supplementary Fig. 3).Becau...

Phosphotidylinositol (PtdIns) signaling is tightly regulated, both spatially and temporally, by subcellularly localized PtdIns kinases and phosphatases that dynamically alter downstream signaling events 1. Joubert Syndrome (JS) characterized by a specific midbrain-hindbrain malformation (“molar tooth sign”) and variably associated retinal dystrophy, nephronophthisis, liver fibrosis and polydactyly 2, and is included in the newly emerging group of “ciliopathies”. In patients linking to JBTS1, we identified mutations in the INPP5E gene, encoding inositol polyphosphate-5-phosphatase E, which hydrolyzes the 5-phosphate of PtdIns(3,4,5)P3 and PtdIns(4,5)P2. Mutations clustered in the phosphatase domain and impaired 5-phosphatase activity, resulting in altered cellular PtdIns ratios. INPP5E localized to cilia in major organs affected in JS, and mutations promoted premature destabilization of cilia in response to stimulation. Thus, these data links PtdIns signaling to the primary cilium, a cellular structure that is becoming increasingly appreciated for its role in mediating cell signals and neuronal function.

Cardiovascular diseases (CVDs) are the leading cause of death worldwide and represent a major problem of public health. Over the years, life expectancy has considerably increased throughout the world, and the prevalence of CVD is inevitably rising with the growing ageing of the population. The normal process of ageing is associated with progressive deterioration in structure and function of the vasculature, commonly called vascular ageing. At the vascular level, extracellular matrix (ECM) ageing leads to molecular alterations in long half-life proteins, such as elastin and collagen, and have critical effects on vascular diseases. This review highlights ECM alterations occurring during vascular ageing with a specific focus on elastin fragmentation and also the contribution of elastin-derived peptides (EDP) in age-related vascular complications. Moreover, current and new pharmacological strategies aiming at minimizing elastin degradation, EDP generation, and associated biological effects are discussed. These strategies may be of major relevance for preventing and/or delaying vascular ageing and its complications.

Background-The role of inflammation at all stages of the atherosclerotic process has become an active area of investigation, and there is a notable quest for novel and innovative drugs for the treatment of atherosclerosis. The lipid kinase phosphoinositide 3-kinase-␥ (PI3K␥) is thought to be a key player in various inflammatory, autoimmune, and allergic processes. These properties and the expression of PI3K␥ in the cardiovascular system suggest that PI3K␥ plays a role in atherosclerosis. Methods and Results-Here, we demonstrate that a specific PI3K␥ inhibitor (AS605240) is effective in murine models of established atherosclerosis. Intraperitoneal administration of AS605240 (10 mg/kg daily) significantly decreased early atherosclerotic lesions in apolipoprotein E-deficient mice and attenuated advanced atherosclerosis in low-density lipoprotein receptor-deficient mice. Furthermore, PI3K␥ levels were elevated in both human and murine atherosclerotic lesions. Comparison of low-density lipoprotein receptor-deficient mice transplanted with wild-type or PI3K␥-deficient bone marrow demonstrated that functional PI3K␥ in the hematopoietic lineage is required for atherosclerotic progression. Alleviation of atherosclerosis by targeting of PI3K␥ activity was accompanied by decreased macrophage and T-cell infiltration, as well as increased plaque stabilization. Conclusions-These data identify PI3K␥ as a new target in atherosclerosis with the potential to modulate multiple stages of atherosclerotic lesion formation, such as fatty streak constitution, cellular composition, and final fibrous cap establishment.