ABSTRACT
Mucus is a biomaterial with peculiar, gel-like viscoelastic properties, and bearing different functionalities, depending on the different mucosae it covers. It is clear that these functionalities have to stay effective throughout the in vivo broad range of physiological pH values at which the mucus is exposed. We sought here to determine the effect of pH on the rheological properties of ex vivo mucus. We demonstrate that viscoelastic properties of gastric mucus are quite "stable" to pH changes, in marked contrast with the pH sensitivity of purified mucin gels. We also find that the rheological features of porcine gastric mucus are reversible when the system is first alkalized up to solubilization (pHâ¯>â¯8.5) and then re-acidified to its initial pH value.
Subject(s)
Elasticity , Mucus , Stomach , Animals , Hydrogen-Ion Concentration , Materials Testing , Swine , ViscosityABSTRACT
The nucleolus is implicated in sensing and responding to cellular stress by stabilizing p53. The pro-apoptotic effect of p53 is associated with several neurodegenerative disorders, including Huntington's disease (HD), which is characterized by the progressive loss of medium spiny neurons (MSNs) in the striatum. Here we show that disruption of nucleolar integrity and function causes nucleolar stress and is an early event in MSNs of R6/2 mice, a transgenic model of HD. Targeted perturbation of nucleolar function in MSNs by conditional knockout of the RNA polymerase I-specific transcription initiation factor IA (TIF-IA) leads to late progressive striatal degeneration, HD-like motor abnormalities and molecular signatures. Significantly, p53 prolongs neuronal survival in TIF-IA-deficient MSNs by transient upregulation of phosphatase and tensin homolog deleted on chromosome 10 (PTEN), a tumor suppressor that inhibits mammalian target of rapamycin signaling and induces autophagy. The results emphasize the initial role of nucleolar stress in neurodegeneration and uncover a p53/PTEN-dependent neuroprotective response.
Subject(s)
Cell Nucleolus/pathology , Corpus Striatum/pathology , Animals , Cell Nucleolus/metabolism , Corpus Striatum/metabolism , Disease Models, Animal , Gene Knockout Techniques , Huntington Disease/genetics , Huntington Disease/metabolism , Huntington Disease/pathology , Male , Mice , Mice, Transgenic , PTEN Phosphohydrolase/biosynthesis , PTEN Phosphohydrolase/genetics , Signal Transduction , Stress, Physiological , TOR Serine-Threonine Kinases/metabolism , Tumor Suppressor Protein p53/biosynthesis , Tumor Suppressor Protein p53/geneticsABSTRACT
cAMP response element binding protein (CREB) and the related factors CREM (cAMP response element modulator) and ATF1 (activation transcription factor 1) are bZIP-domain-containing transcription factors activated through cAMP and other signaling pathways. The disruption of CREB function in developing and mature neurons affects their development and survival when associated with loss of CREM. Since dopaminergic (DA) neurons are affected in several neurological diseases, we generated CREB conditional mutants in DA neurons by using a newly generated transgenic Cre line targeting the dopaminergic system (DATCre). Here we report the generation and analysis of mutant mice lacking CREB in DA neurons (CREB(DATCre) mutants). During adulthood, lack of CREB leads to a partial loss of DA neurons. Since CREM is upregulated in absence of CREB, we have introduced this mutation in a CREM-/- genetic background to assess a compensatory role of CREM. Additional inactivation of CREM does not lead to a more severe phenotype.
Subject(s)
Cell Survival , Cyclic AMP Response Element Modulator/physiology , Cyclic AMP Response Element-Binding Protein/physiology , Gene Expression Regulation, Developmental , Neurons/metabolism , Animals , Cyclic AMP/metabolism , Cyclic AMP Response Element Modulator/genetics , Cyclic AMP Response Element-Binding Protein/genetics , Immunoenzyme Techniques , In Situ Hybridization , Mice , Mice, Knockout , Mice, Transgenic , Neurons/cytology , Signal Transduction , Transcription, Genetic , Transcriptional Activation , Up-RegulationABSTRACT
The thyroid-stimulating hormone/thyrotropin (TSH) is the most relevant hormone in the control of thyroid gland physiology in adulthood. TSH effects on the thyroid gland are mediated by the interaction with a specific TSH receptor (TSHR). We studied the role of TSHTSHR signaling on gland morphogenesis and differentiation in the mouse embryo using mouse lines deprived either of TSH (pit(dw)pit(dw)) or of a functional TSHR (tshr(hyt)tshr(hyt) and TSHR-knockout lines). The results reported here show that in the absence of either TSH or a functional TSHR, the thyroid gland develops to a normal size, whereas the expression of thyroperoxidase and the sodium/iodide symporter are reduced greatly. Conversely, no relevant changes are detected in the amounts of thyroglobulin and the thyroid-enriched transcription factors TTF-1, TTF-2, and Pax8. These data suggest that the major role of the TSH/TSHR pathway is in controlling genes involved in iodide metabolism such as sodium/iodide symporter and thyroperoxidase. Furthermore, our data indicate that in embryonic life TSH does not play an equivalent role in controlling gland growth as in the adult thyroid.
