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Giovanni Camussi - One of the best experts on this subject based on the ideXlab platform.
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neural cell adhesion molecule ncam expression by immature and tumor derived endothelial cells favors cell organization into capillary like structures
Experimental Cell Research, 2006Co-Authors: Benedetta Bussolati, Stefano Buttiglieri, Maria Chiara Deregibus, Cristina Grange, Stefania Bruno, Lorenzo Tei, Silvio Aime, Giovanni CamussiAbstract:The neural cell adhesion molecule (NCAM) is widely expressed during embryogenesis, down-regulated in the course of differentiation to be re-expressed during progression of some tumors. We here found that renal tumor-derived endothelial cells (TEC) but not normal endothelial cells (HMEC) expressed NCAM. In TEC, NCAM expression was regulated by the renal embryonic Transcription Factor PAX2, as transfection with PAX2 antisense abrogated NCAM expression. NCAM stimulation with an agonistic synthetic NCAM peptide enhanced apoptosis resistance and increased ability of TEC to organize in vessel-like structures. The angiogenic effect of NCAM peptide was, at least in part, mediated by the association of NCAM and FGFR1. HMEC transiently acquired NCAM when organized in vessel-like structures after VEGF stimulation or when transfected with PAX2 gene. During the process of VEGF-induced endothelial differentiation of renal stem cells and of circulating endothelial progenitors, NCAM was transiently expressed to disappear at complete endothelial maturation. Targeting NCAM with a saporin-conjugated peptide induced a cytotoxic effect on TEC but not on HMEC. In conclusion, we identified a new role of NCAM in tumor neo-angiogenesis relevant for endothelial cell organization into capillary-like structures. In addition, we found that NCAM expression was associated with an immature phenotype of endothelial cells.
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expression of PAX2 in human renal tumor derived endothelial cells sustains apoptosis resistance and angiogenesis
American Journal of Pathology, 2006Co-Authors: Valentina Fonsato, Stefano Buttiglieri, Maria Chiara Deregibus, Valeria Puntorieri, Benedetta Bussolati, Giovanni CamussiAbstract:The Transcription Factor PAX2 is known to play a key role during renal development and to act as an oncogene favoring renal tumor growth. We recently showed that endothelial cells derived from human renal carcinomas display abnormal characteristics of survival and angiogenic properties. In the present study we found that renal tumor-derived endothelial cells, but not normal endothelial cells, expressed PAX2 protein and mRNA. To down-regulate PAX2 expression, we transfected tumor-derived endothelial cells with an anti-sense PAX2 vector whereas we transfected normal human microvascular endothelial cells with a sense PAX2 vector to induce PAX2 expression. The inhibition of PAX2 expression in tumor-derived endothelial cells induced an increase in tumor suppressor PTEN expression and a decrease in Akt phosphorylation. In addition, decreased apoptosis resistance, adhesion, invasion, and in vitro and in vivo angiogenesis were observed. Conversely, PAX2 induction in normal endothelial cells conferred to these cells a proinvasive, proangiogenic phenotype similar to that of tumor-derived endothelial cells. These results indicate that PAX2 is involved in renal tumor angiogenesis and its expression may antagonize that of the PTEN tumor suppressor gene, affecting the Akt-survival pathway and promoting angiogenesis.
Andrew J Todd - One of the best experts on this subject based on the ideXlab platform.
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preprotachykinin a is expressed by a distinct population of excitatory neurons in the mouse superficial spinal dorsal horn including cells that respond to noxious and pruritic stimuli
Pain, 2017Co-Authors: Maria Gutierrezmecinas, Andrew M Bell, Alina Marin, Rebecca Taylor, Kieran A Boyle, Takahiro Furuta, Masahiko Watanabe, Erika Polgar, Andrew J ToddAbstract:The superficial dorsal horn, which is the main target for nociceptive and pruritoceptive primary afferents, contains a high density of excitatory interneurons. Our understanding of their roles in somatosensory processing has been restricted by the difficulty of distinguishing functional populations among these cells. We recently defined 3 nonoverlapping populations among the excitatory neurons, based on the expression of neurotensin, neurokinin B, and gastrin-releasing peptide. Here we identify and characterise another population: neurons that express the tachykinin peptide substance P. We show with immunocytochemistry that its precursor protein (preprotachykinin A, PPTA) can be detected in ∼14% of lamina I-II neurons, and these are concentrated in the outer part of lamina II. Over 80% of the PPTA-positive cells lack the Transcription Factor PAX2 (which determines an inhibitory phenotype), and these account for ∼15% of the excitatory neurons in this region. They are different from the neurotensin, neurokinin B, or gastrin-releasing peptide neurons, although many of them contain somatostatin, which is widely expressed among superficial dorsal horn excitatory interneurons. We show that many of these cells respond to noxious thermal and mechanical stimuli and to intradermal injection of pruritogens. Finally, we demonstrate that these cells can also be identified in a knock-in Cre mouse line (Tac1), although our findings suggest that there is an additional population of neurons that transiently express PPTA. This population of substance P-expressing excitatory neurons is likely to play an important role in the transmission of signals that are perceived as pain and itch.
Andrew K. Groves - One of the best experts on this subject based on the ideXlab platform.
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notch signaling augments the canonical wnt pathway to specify the size of the otic placode
Development, 2008Co-Authors: Chathurani S Jayasena, Takahiro Ohyama, Neil Segil, Andrew K. GrovesAbstract:The inner ear derives from a patch of ectoderm defined by expression of the Transcription Factor PAX2. We recently showed that this PAX2^+ ectoderm gives rise not only to the otic placode but also to the surrounding cranial epidermis, and that Wnt signaling mediates this placode-epidermis fate decision. We now present evidence for reciprocal interactions between the Wnt and Notch signaling pathways during inner ear induction. Activation of Notch1 in PAX2+ ectoderm expands the placodal epithelium at the expense of cranial epidermis, whereas loss of Notch1 leads to a reduction in the size of the otic placode. We show that Wnt signaling positively regulates Notch pathway genes such as Jag1, Notch1 and Hes1, and we have used transgenic Wnt reporter mice to show that Notch signaling can modulate the canonical Wnt pathway. Gain- and loss-of-function mutations in the Notch and Wnt pathways reveal that some aspects of otic placode development - such as Pax8 expression and the morphological thickening of the placode - can be regulated independently by either Notch or Wnt signals. Our results suggest that Wnt signaling specifies the size of the otic placode in two ways, by directly upregulating a subset of otic genes, and by positively regulating components of the Notch signaling pathway, which then act to augment Wnt signaling.
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wnt signals mediate a fate decision between otic placode and epidermis
Development, 2006Co-Authors: Takahiro Ohyama, Othman A Mohamed, Makoto Mark Taketo, Daniel Dufort, Andrew K. GrovesAbstract:The otic placode, the anlagen of the inner ear, develops from an ectodermal field characterized by expression of the Transcription Factor PAX2 . Previous fate mapping studies suggest that these PAX2+ cells will give rise to both otic placode tissue and epidermis, but the signals that divide the PAX2+ field into placodal and epidermal territories are unknown. We report that Wnt signaling is normally activated in a subset of PAX2+ cells, and that conditional inactivation of β-catenin in these cells causes an expansion of epidermal markers at the expense of the otic placode. Conversely, conditional activation of β-catenin in PAX2+ cells causes an expansion of the otic placode at the expense of epidermis, and the resulting otic tissue expresses exclusively dorsal otocyst markers. Together, these results suggest that Wnt signaling acts instructively to direct PAX2+ cells to an otic placodal, rather than an epidermal, fate and promotes dorsal cell identities in the otocyst.
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wnt signals mediate a fate decision between otic placode and epidermis
Development, 2006Co-Authors: Takahiro Ohyama, Othman A Mohamed, Makoto Mark Taketo, Daniel Dufort, Andrew K. GrovesAbstract:The otic placode, the anlagen of the inner ear, develops from an ectodermal field characterized by expression of the Transcription Factor PAX2. Previous fate mapping studies suggest that these PAX2(+) cells will give rise to both otic placode tissue and epidermis, but the signals that divide the PAX2(+) field into placodal and epidermal territories are unknown. We report that Wnt signaling is normally activated in a subset of PAX2(+) cells, and that conditional inactivation of beta-catenin in these cells causes an expansion of epidermal markers at the expense of the otic placode. Conversely, conditional activation of beta-catenin in PAX2(+) cells causes an expansion of the otic placode at the expense of epidermis, and the resulting otic tissue expresses exclusively dorsal otocyst markers. Together, these results suggest that Wnt signaling acts instructively to direct PAX2(+) cells to an otic placodal, rather than an epidermal, fate and promotes dorsal cell identities in the otocyst.
Maria Gutierrezmecinas - One of the best experts on this subject based on the ideXlab platform.
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preprotachykinin a is expressed by a distinct population of excitatory neurons in the mouse superficial spinal dorsal horn including cells that respond to noxious and pruritic stimuli
Pain, 2017Co-Authors: Maria Gutierrezmecinas, Andrew M Bell, Alina Marin, Rebecca Taylor, Kieran A Boyle, Takahiro Furuta, Masahiko Watanabe, Erika Polgar, Andrew J ToddAbstract:The superficial dorsal horn, which is the main target for nociceptive and pruritoceptive primary afferents, contains a high density of excitatory interneurons. Our understanding of their roles in somatosensory processing has been restricted by the difficulty of distinguishing functional populations among these cells. We recently defined 3 nonoverlapping populations among the excitatory neurons, based on the expression of neurotensin, neurokinin B, and gastrin-releasing peptide. Here we identify and characterise another population: neurons that express the tachykinin peptide substance P. We show with immunocytochemistry that its precursor protein (preprotachykinin A, PPTA) can be detected in ∼14% of lamina I-II neurons, and these are concentrated in the outer part of lamina II. Over 80% of the PPTA-positive cells lack the Transcription Factor PAX2 (which determines an inhibitory phenotype), and these account for ∼15% of the excitatory neurons in this region. They are different from the neurotensin, neurokinin B, or gastrin-releasing peptide neurons, although many of them contain somatostatin, which is widely expressed among superficial dorsal horn excitatory interneurons. We show that many of these cells respond to noxious thermal and mechanical stimuli and to intradermal injection of pruritogens. Finally, we demonstrate that these cells can also be identified in a knock-in Cre mouse line (Tac1), although our findings suggest that there is an additional population of neurons that transiently express PPTA. This population of substance P-expressing excitatory neurons is likely to play an important role in the transmission of signals that are perceived as pain and itch.
Saji Abraham - One of the best experts on this subject based on the ideXlab platform.
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epigenetic regulation of arginine vasopressin receptor 2 expression by PAX2 and pax Transcription interacting protein
American Journal of Physiology-renal Physiology, 2021Co-Authors: Saji Abraham, Raghavendra Paknikar, Samina Bhumbra, Danny Luan, Madhusudan Venkatareddy, Christopher L Oconnor, Markus Bitzer, Robert A Fenton, Toby W HurdAbstract:Renal arginine vasopressin receptor 2 (AVPR2) plays a crucial role in osmoregulation. Engagement of ligand with AVPR2 results in aquaporin 2 movement to the apical membrane and water reabsorption from the urinary filtrate. Despite this essential role, little is known about Transcriptional regulation of Avpr2. Here, we identify novel roles for PAX2, a Transcription Factor crucial for kidney development, and its adaptor protein, Pax Transcription interacting protein (PTIP), for epigenetic regulation of Avpr2 and thus body water balance. Chromatin immunoprecipitation (ChIP) from murine inner medulla cells (IMCD-3) identified the minimal DNA-binding region of PAX2 on the Avpr2 promoter. Regulation of Avpr2 by PAX2 was confirmed using a heterologous DNA expression system. PAX2 recruits the adaptor protein PTIP and its associated histone methyltransferase (HMT) complex to Avpr2 promoter, imposing epigenetic marks on this region and throughout the coding sequence that modulate Avpr2 gene Transcription. Reduction of PAX2 or PTIP protein levels by siRNA prevented histone lysine methylation and expression of Avpr2. ChIP using mouse or human kidneys determined that PAX2 is highly enriched in the AVPR2 promoter alongside PTIP and HMT proteins, leading to high levels of histone H3 lysine trimethylation within the promoter and throughout the gene. In conclusion, PAX2 provides locus specificity for PTIP, allowing the HMT complex to impart epigenetic changes at the Avpr2 locus and regulate Avpr2 Transcription. These finding have major implications for understanding regulation of body water balance.NEW & NOTEWORTHY The Transcription Factor PAX2 plays an indispensable role in kidney development. In the adult kidney, we identified the first described protein this protein regulates. PAX2 and its interacting partner Pax Transcription interacting protein recruit a histone methyltransferase complex to the promoter and epigentically regulate the expression of arginine vasopressin receptor 2, a protein that plays a crucial role in osmoregulation in the distal tubule.
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PAX2 and pax8 proteins regulate urea transporters and aquaporins to control urine concentration in the adult kidney
Journal of The American Society of Nephrology, 2020Co-Authors: Ann M Laszczyk, Craig N Johnson, Atsuko Y Higashi, Abdul Soofi, Saji AbrahamAbstract:BACKGROUND: As the glomerular filtrate passes through the nephron and into the renal medulla, electrolytes, water, and urea are reabsorbed through the concerted actions of solute carrier channels and aquaporins at various positions along the nephron and in the outer and inner medulla. Proliferating stem cells expressing the nuclear Transcription Factor PAX2 give rise to renal epithelial cells. PAX2 expression ends once the epithelial cells differentiate into mature proximal and distal tubules, whereas expression of the related Pax8 protein continues. The collecting tubules and renal medulla are derived from PAX2-positive ureteric bud epithelia that continue to express PAX2 and Pax8 in adult kidneys. Despite the crucial role of PAX2 in renal development, functions for PAX2 or Pax8 in adult renal epithelia have not been established. METHODS: To examine the roles of PAX2 and Pax8 in the adult mouse kidney, we deleted either PAX2, Pax8, or both genes in adult mice and examined the resulting phenotypes and changes in gene expression patterns. We also explored the mechanism of Pax8-mediated activation of potential target genes in inner medullary collecting duct cells. RESULTS: Mice with induced deletions of both PAX2 and Pax8 exhibit severe polyuria that can be attributed to significant changes in the expression of solute carriers, such as the urea transporters encoded by Slc14a2, as well as aquaporins within the inner and outer medulla. Furthermore, Pax8 expression is induced by high-salt levels in collecting duct cells and activates the Slc14a2 gene by recruiting a histone methyltransferase complex to the promoter. CONCLUSIONS: These data reveal novel functions for Pax proteins in adult renal epithelia that are essential for retaining water and concentrating urine.
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the groucho associated phosphatase ppm1b displaces pax transactivation domain interacting protein ptip to switch the Transcription Factor PAX2 from a Transcriptional activator to a repressor
Journal of Biological Chemistry, 2015Co-Authors: Saji Abraham, Raghavendra Paknikar, Samina Bhumbra, Danny Luan, Rohan Garg, Sanjeevkumar R. PatelAbstract:Pax genes encode developmental regulatory proteins that specify cell lineages and tissues in metazoans. Upon binding to DNA through the conserved paired domain, Pax proteins can recruit both activating and repressing complexes that imprint distinct patterns of histone methylation associated with either gene activation or silencing. How the switch from Pax-mediated activation to repression is regulated remains poorly understood. In this report, we identify the phosphatase PPM1B as an essential component of the Groucho4 repressor complex that is recruited by PAX2 to chromatin. PPM1B can dephosphorylate the PAX2 activation domain and displace the adaptor protein PTIP, thus inhibiting H3K4 methylation and gene activation. Loss of PPM1B prevents Groucho-mediated gene repression. Thus, PPM1B helps switch PAX2 from a Transcriptional activator to a repressor protein. This can have profound implications for developmental regulation by Pax proteins and suggests a model for imprinting specific epigenetic marks depending on the availability of co-Factors.