YAP (yes-associated protein) is a transcriptional factor that is negatively regulated by Hippo pathway, a conserved pathway for the development and size control of multiple organs. The exact function ...of YAP in bone homeostasis remains controversial. Here we provide evidence for YAP's function in promoting osteogenesis, suppressing adipogenesis, and thus maintaining bone homeostasis. YAP is selectively expressed in osteoblast (OB)-lineage cells. Conditionally knocking out
in the OB lineage in mice reduces cell proliferation and OB differentiation and increases adipocyte formation, resulting in a trabecular bone loss. Mechanistically, YAP interacts with β-catenin and is necessary for maintenance of nuclear β-catenin level and Wnt/β-catenin signaling. Expression of β-catenin in YAP-deficient BMSCs (bone marrow stromal cells) diminishes the osteogenesis deficit. These results thus identify YAP-β-catenin as an important pathway for osteogenesis during adult bone remodeling and uncover a mechanism underlying YAP regulation of bone homeostasis.
•Rapsyn - a multi-domain protein.•Roles in AChR clustering.•An adapter for AChR anchoring.•E3 ligase activity for AChR clustering and NMJ formation.•Rapsyn as signaling molecule.
The acetylcholine ...receptor (AChR) is highly concentrated at the neuromuscular junction (NMJ), ensuring efficient signal transmission from motoneurons to muscle fibers. This requires the agrin-LRP4-MuSK signaling as well as rapsyn, a peripheral, intracellular protein that is enriched at the NMJ. Mutations of rapsyn have been associated with NMJ diseases including congenital myasthenia syndromes. Rapsyn is a prototype of synaptic adaptor proteins that is thought to bind and anchor neurotransmitter receptors to the postsynaptic membrane. In accord, it interacts with the AChR and a plethora of proteins that associate or regulate the cytoskeleton. Rapsyn also interacts with signaling molecules. Recent studies show that it possesses E3 ligase activity that is required for NMJ formation, revealing a novel function of this classic adaptor protein. Identifying rapsyn as a signaling molecule provides a handle in studies of mechanisms of NMJ formation, maintenance, aging and disorders.
LRP4 Serves as a Coreceptor of Agrin Zhang, Bin; Luo, Shiwen; Wang, Qiang ...
Neuron (Cambridge, Mass.),
10/2008, Letnik:
60, Številka:
2
Journal Article
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Odprti dostop
Neuromuscular junction (NMJ) formation requires agrin, a factor released from motoneurons, and MuSK, a transmembrane tyrosine kinase that is activated by agrin. However, how signal is transduced from ...agrin to MuSK remains unclear. We report that LRP4, a low-density lipoprotein receptor (LDLR)-related protein, is expressed specifically in myotubes and binds to neuronal agrin. Its expression enables agrin binding and MuSK signaling in cells that otherwise do not respond to agrin. Suppression of LRP4 expression in muscle cells attenuates agrin binding, agrin-induced MuSK tyrosine phosphorylation, and AChR clustering. LRP4 also forms a complex with MuSK in a manner that is stimulated by agrin. Finally, we showed that LRP4 becomes tyrosine-phosphorylated in agrin-stimulated muscle cells. These observations indicate that LRP4 is a coreceptor of agrin that is necessary for MuSK signaling and AChR clustering and identify a potential target protein whose mutation and/or autoimmunization may cause muscular dystrophies.
Yes-associated protein (YAP) is a key transcriptional cofactor of the Hippo pathway, critical for the development of multiple organs. However, its role in the developing brain remains poorly ...understood. Here, we found that YAP was highly expressed in astrocytes and YAP deletion elevated the astrocytic activation in culture and in vivo, which was associated with microglial activation. At the molecular level, YAP in astrocytes was activated by IFNβ or ciliary neurotrophic factor (CNTF), which was necessary for IFNβ or CNTF induction of the suppressor of cytokine signaling 3 (SOCS3), a negative regulator of the Janus kinase-signal transducer and activator of transcription (JAK-STAT) inflammatory pathway. YAP(-/-) astrocytes thus showed hyperactivation of the JAK-STAT inflammatory pathway and reactive astrogliosis. Expression of SOCS3 in YAP(-/-) astrocytes prevented the hyperactivation of STAT3 and partially restored the astrocytic activation. Finally, reactive astrogliosis was associated with blood-brain barrier dysfunction in YAP brain-selective knockout mice. Taken together, these results identify unrecognized functions of YAP in preventing reactive astrogliosis and reveal a pathway of YAP-SOCS for the negatively control of neuroinflammation.
We report the largely improved electrochemical capacitance of polypyrrole-derived microporous carbon nanospheres (MCNs, 80-100 nm in diameter) containing nitrogen functional groups. We have ...investigated the electrochemical properties of precursor polypyrrole nanospheres (PNs, with a high N/C ratio and low surface area) and as-derived carbon nanospheres (CNs, with a moderate N/C ratio and low surface area) prepared by carbonizing PNs at different temperatures, and MCNs (with a low N/C ratio and high surface area) obtained by chemical activation of CNs. The samples are thoroughly characterized by transmission electron microscopy (TEM), X-ray diffraction (XRD), Raman spectroscopy, thermogravimetric analysis (TGA), nitrogen sorption, elemental analysis, and X-ray photoelectron spectroscopy (XPS). It is found that MCNs with a high surface area and N-doping species exhibit much better capacitive performance compared to the PNs and CNs, and commercial carbon blacks (XC-72 and BP2000) as well. The MCN sample gives a reversible specific capacitance of similar240 F g-1 for 3000 cycles in aqueous media as a result of combined advantages of high electrochemical activity of doped heteroatoms (N and O) and accessible well-developed porosity, demonstrating the promising use in high-energy-density supercapacitors.
The nuclear lamina protein lamin A/C is a key component of the nuclear envelope. Mutations in the lamin A/C gene (LMNA) are identified in patients with various types of laminopathy-containing ...diseases, which have features of accelerated aging and osteoporosis. However, the underlying mechanisms for laminopathy-associated osteoporosis remain largely unclear. Here, we provide evidence that loss of lamin A/C in skeletal muscles, but not osteoblast (OB)-lineage cells, results in not only muscle aging-like deficit but also trabecular bone loss, a feature of osteoporosis. The latter is due in large part to elevated bone resorption. Further cellular studies show an increase of osteoclast (OC) differentiation in cocultures of bone marrow macrophages/monocytes (BMMs) and OBs after treatment with the conditioned medium (CM) from lamin A/C-deficient muscle cells. Antibody array screening analysis of the CM proteins identifies interleukin (IL)-6, whose expression is markedly increased in lamin A/C-deficient muscles. Inhibition of IL-6 by its blocking antibody in BMM-OB cocultures diminishes the increase of osteoclastogenesis. Knockout (KO) of IL-6 in muscle lamin A/C-KO mice diminishes the deficits in trabecular bone mass but not muscle. Further mechanistic studies reveal an elevation of cellular senescence marked by senescence-associated beta-galactosidase (SA-β-gal), p16Ink4a, and p53 in lamin A/C-deficient muscles and C2C12 muscle cells, and the p16Ink4a may induce senescence-associated secretory phenotype (SASP) and IL-6 expression. Taken together, these results suggest a critical role for skeletal muscle lamin A/C to prevent cellular senescence, IL-6 expression, hyperosteoclastogenesis, and trabecular bone loss, uncovering a pathological mechanism underlying the link between muscle aging/senescence and osteoporosis.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
YAP (yes-associated protein), a key transcriptional co-factor that is negatively regulated by the Hippo pathway, is crucial for the development and size control of multiple organs, including the ...liver. However, its role in the brain remains unclear. Here, we provide evidence for YAP regulation of mouse neocortical astrocytic differentiation and proliferation. YAP was undetectable in neurons, but selectively expressed in neural stem cells (NSCs) and astrocytes. YAP in NSCs was required for neocortical astrocytic differentiation, with no apparent role in self-renewal or neural differentiation. However, YAP in astrocytes was necessary for astrocytic proliferation. Yap (Yap1) knockout, Yap(nestin) conditional knockout and Yap(GFAP) conditional knockout mice displayed fewer neocortical astrocytes and impaired astrocytic proliferation and, consequently, death of neocortical neurons. Mechanistically, YAP was activated by BMP2, and the active/nuclear YAP was crucial for BMP2 induction and stabilization of SMAD1 and astrocytic differentiation. Expression of SMAD1 in YAP-deficient NSCs partially rescued the astrocytic differentiation deficit in response to BMP2. Taken together, these results identify a novel function of YAP in neocortical astrocytic differentiation and proliferation, and reveal a BMP2-YAP-SMAD1 pathway underlying astrocytic differentiation in the developing mouse neocortex.
Maize/peanut intercropping system shows the significant yield advantage. Soil microbes play major roles in soil nutrient cycling and were affected by intercropping plants. This experiment was carried ...out to evaluate the changing of rhizosphere microbial community composition, and the relationship between microbial community and soil enzymatic activities, soil nutrients in maize/peanut intercropping system under the following three treatments： maize （Zea mays L.） and peanut （Arachis hypogaea L.） were intercropped without any separation （NS）, by half separation （HS） using a nylon net （50 μm） and complete separation （CS） by using a plastic sheet, respectively. The soil microbial communities were assessed by phospholipid fatty acid （PLFA）. We found that soil available nutrients （available nitrogen （Avail N） and available phosphorus （Avail P）） and enzymatic activities （soil urase and phosphomonoesterase） in both crops were improved in NS and HS treatments as compared to CS. Both bacterial and fungal biomasses in both crops were increased in NS followed by HS. Furthermore, Gram-positive bacteria （G＋） in maize soils were significant higher in NS and HS than CS, while the Gram-negative （G-） was significant higher in peanut soil. The ratio of normal saturated to monounsaturated PLFAs was significantly higher in rhizosphere of peanut under CS treatment than in any other treatments, which is an indicator of nutrient stress. Redundancy analysis and cluster analysis of PLFA showed rhizospheric microbial community of NS and HS of both plants tended to be consistent. The urase and Avail N were higher in NS and HS of both plants and positively correlated with bacteria, fungi （F） and total PLFAs, while negatively correlated with G＋/G- and NS/MS. The findings suggest that belowground interactions in maize/peanut intercropping system play important roles in changing the soil microbial composition and the dominant microbial species, which was closely related with the improving of soil available nutrients （N and P） and enzymatic activities.
Abstract Low-density lipoprotein receptor-related protein 4 (LRP4) is a member of the low-density lipoprotein receptor (LDLR) family. Recent studies have revealed multiple functions and complex ...signaling mechanisms of LRP4 in different organs and tissues. LPR4 mutation or malfunction has been implicated in neurological disorders including congenital myasthenic syndrome, myasthenia gravis, and diseases of bone or kidney. This article is part of a Special Issue entitled “Muscle Bone Interactions”.
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