molecules involved with synaptic vesicle trafficking and connectivity and enzymes that are directly involved with major signal transduction pathways, such as MAP kinase phosphatases. What is the relevance of these alterations in BDNF-regulated transcription Neurotrophins, such as BDNF are critical in modulating synaptic plasticity, in addition to their wellestablished roles in neuronal cell survival. Application of neurotrophins to peripheral and central neurons results in rapid increases in the frequency of spontaneous action potentials and excitatory synaptic activity. One of the most important mechanisms for cellular response to extrinsic factors is through G protein signaling. G protein-coupled receptors are highly relevant to OB differentiation and function, as evidenced by the get SKI II anabolic skeletal response to parathyroid hormone and prostaglandin E, two agents that act on GPCRs presented on OB lineage cells. Genetic studies in human and mice further support the key role played by G protein signaling. We described a number of transgenic mouse models in which G protein coupled signaling has been manipulated in vivo in OBs that express the 2.3 kb-Col I promoter. These models include OB-specific expression of an engineered constitutively active Gs-coupled receptor, Rs1, and OB-specific expression of pertussis toxin to block Gi signaling; both of which demonstrate an anabolic bone phenotype. Mice expressing Rs1, showed an increase in bone accrual within the skull and in femur size, assessed by the whole body microCT analysis, with a dramatic age-dependent increase in trabecular bone with features resembling fibrous dysplasia. At 9 weeks of age, the male and female mutant mice showed dramatic increases in whole-body areal bone mineral density, as determined by dual-energy x-ray absorptiometry scanning. Histological assessment of femoral bones indicated that there was an increase in OB lineage cells, especially immature OBs, indicated by an expansion of cells expressing early OB markers, Exp Cell Res. Author manuscript; available in PMC 2016 May 01. Wattanachanya et al. Page 3 Runx2 and Osterix. Increased osteoclast activity was suggested by the large number of tartrate-resistant acid phosphatase -positive regions adjacent to the trabeculi within the lesions. Bone tissue quality; mineralization, composition, and maturity, of calvariae and femurs in Rs1 mice were also assessed by the complementary techniques of fourier transform infrared spectroscopy and synchrotron radiation micro-computed tomography . We demonstrated that mineral-to-matrix ratio and cross-link ratio were significantly lower in 6- and 15-week mutant bones. No differences in FTIR spectroscopic parameters were detected between the two anatomic sites despite the different bone-formation processes. Tissue mineral density was also significantly lower in 3- and 9-week transgenic femoral diaphyses. The results indicate that continuous Gs activation in mature OBs lead to deposition of immature bone tissue with reduced mineralization. The ability of Rs1 signaling in mature OBs to drive expansion of immature OBs could be mediated by paracrine factors, secreted from mature OBs that influence early OB commitment, differentiation, and/or proliferation. However, little is known about the in vivo cellular basis of the skeletal changes in response to enhanced Gs signaling in mature OBs. In this study, we determined how Gs signaling in mature OBs affects bone formation by PubMed ID:,22102576 examining the Rs1

These data indicate that SRPK1 is essential for early embryonic development in the mouse

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