scholarly journals The ulnar-mammary syndrome gene, Tbx3, is a direct target of the retinoic acid signaling pathway, which regulates its expression during mouse limb development

2012 ◽  
Vol 23 (12) ◽  
pp. 2362-2372 ◽  
Author(s):  
Reyna Deeya Ballim ◽  
Cathy Mendelsohn ◽  
Virginia E. Papaioannou ◽  
Sharon Prince
Keyword(s):  
Retinoic Acid ◽  
Signaling Pathway ◽  
Limb Development ◽  
Postnatal Life ◽  
Functional Protein ◽  
Embryonic Limb ◽  
Mouse Limb ◽  
Direct Target

TBX3, a member of the T-box transcription factor gene family, is a transcriptional repressor that is required for the development of the heart, limbs, and mammary glands. Mutations in TBX3 that result in reduced functional protein lead to ulnar-mammary syndrome, a developmental disorder characterized by limb, mammary gland, tooth, and genital abnormalities. Increased levels of TBX3 have been shown to contribute to the oncogenic process, and TBX3 is overexpressed in several cancers, including breast cancer, liver cancer, and melanoma. Despite its important role in development and postnatal life, little is known about the signaling pathways that modulate TBX3 expression. Here we show, using in vitro and in vivo assays, that retinoic acid (RA) activates endogenous TBX3 expression, which is mediated by an RA–receptor complex directly binding and activating the TBX3 promoter, and we provide evidence that this regulation may be functionally relevant in mouse embryonic limb development. Our data identify TBX3 as a direct target of the RA signaling pathway and extend our understanding of the role and regulation of TBX3 in limb development.

Vitamin A alters the internal viscosity of fragments of limb-bud mesenchyme

Development ◽  
1980 ◽  
Vol 59 (1) ◽  
pp. 325-339
Author(s):  
T. E. Kwasigroch ◽  
D. M. Kochhar
Keyword(s):  
Retinoic Acid ◽  
Vitamin A ◽  
Mesenchymal Cells ◽  
Limb Bud ◽  
Mouse Limb ◽  
Vitamin A Acid ◽  
Internal Viscosity ◽  
Fusion Experiments

Two techniques were used to examine the effect of vitamin A compounds (vitamin A acid = retinoic acid and vitamin A acetate) upon the relative strengths of adhesion among mouse limb-bud mesenchymal cells. Treatment with retinoic acid in vivo and with vitamin A acetate in vitro reduced the rate at which the fragments of mesenchyme rounded-up when cultured on a non-adhesive substratum, but these compounds did not alter the behavior of tissues tested in fragment-fusion experiments. These conflicting results indicate that the two tests measure different activities of cells and suggest that treatment with vitamin A alters the property(ies) of cells which regulate the internal viscosity of tissues.

Changes in expression of the lysosomal membrane glycoprotein, LAMP-1 in interdigital regions during embryonic mouse limb development, in vivo and in vitro

2000 ◽  
Vol 201 (6) ◽  
pp. 483-490 ◽  
Author(s):  
Sharon Stewart ◽  
Scott Yi ◽  
Garo Kassabian ◽  
Mark Mayo ◽  
Anthony Sank ◽  
...  
Keyword(s):  
Limb Development ◽  
Lysosomal Membrane ◽  
Membrane Glycoprotein ◽  
Embryonic Mouse ◽  
Mouse Limb ◽  
Lysosomal Membrane Glycoprotein

Limb development in mouse embryos: protection against teratogenic effects of 6-diazo-5 oxo-L-norleucine (DON) in vivo and in vitro

Development ◽  
1975 ◽  
Vol 33 (2) ◽  
pp. 355-370
Author(s):  
R. M. Greene ◽  
D. M. Kochhar
Keyword(s):  
Limb Development ◽  
Cleft Lip ◽  
Phenotypic Expression ◽  
Limb Bud ◽  
Concurrent Administration ◽  
Median Cleft ◽  
Mouse Limb ◽  
Limb Malformations

The glutamine analogue, 6-diazo-5-oxo-L-norleucine (DON), has been shown to inhibit biosynthesis of purines and glycosaminoglycans, presumably by blocking the glutaminedependent steps in the biosynthetic pathways. The teratogenic potential of DON on the developing mouse limb-bud in vivo and in vitro was studied in an attempt to discriminate whether DON is exerting its teratogenic effect by interfering with glycosaminoglycan orpurine metabolism. A single intramuscular injection of DON (0·5 mg/kg) to ICR/DUB mice on day 10 of gestation resulted in 76% resorption, while fetuses surviving to day 17 exhibited growth retardation, median cleft lip, and limb malformations. Concurrent administration of Lglutamine (250 mg/kg) provided no protection against resorption or malformations, while 5-aminoimidazolecarboxamide (AIC, 250 mg/kg) decreased the resorption rate to 34% without significantly altering the incidence of malformations. Injection of DON alone on day 11 resulted in 87% of fetuses exhibiting limb malformations, with only 2% resorption. Concurrent injection of AIC decreased the frequency of limb malformations to 32%. L-Glutamine, D-glucosamine, or inosinic acid were without any protective effect in vivo. DON (5 μg/ml medium) added in vitro to organ cultures of day 11 mouse limb-buds caused all limbs to evidence cartilage abnormalities. In this system, either L-glutamine or D-glucosamine (0·5 mg/ml medium) provided protection against DON effects while AIC (0·5 mg/ml medium) offered no protection in vitro. These data suggest that DON exerts its effects in vivo by interfering with purine metabolism while in vitro its teratogenic action may be interruption of glycosaminoglycan biosynthesis. This may reflect upon the relative importance of growth and differentiation to limb development in vivo and in vitro. These data infer that limb development in vitro relies more on the differentiative process (differentiation of cartilage) than on growth, whereas limb development in vivo is dependent, at this stage, to a greater extent on growth for normal phenotypic expression.

scholarly journals Umbilical mesenchymal stem cell-derived exosomes facilitate spinal cord functional recovery through the miR-199a-3p/145-5p-mediated NGF/TrkA signaling pathway in rats

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Yang Wang ◽  
Xunwei Lai ◽  
Depeng Wu ◽  
Bin Liu ◽  
Nanxiang Wang ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Neurite Outgrowth ◽  
Signaling Pathway ◽  
Direct Interaction ◽  
Lesion Size ◽  
Human Umbilical Cord ◽  
Cord Injury ◽  
Direct Target

Abstract Background Although exosomes, as byproducts of human umbilical cord mesenchymal stem cells (hUC-MSCs), have been demonstrated to be an effective therapy for traumatic spinal cord injury (SCI), their mechanism of action remains unclear. Methods We designed and performed this study to determine whether exosomes attenuate the lesion size of SCI by ameliorating neuronal injury induced by a secondary inflammatory storm and promoting neurite outgrowth. We determined the absolute levels of all exosomal miRNAs and investigated the potential mechanisms of action of miR-199a-3p/145-5p in inducing neurite outgrowth in vivo and in vitro. Results miR-199a-3p/145-5p, which are relatively highly expressed miRNAs in exosomes, promoted PC12 cell differentiation suppressed by lipopolysaccharide (LPS) in vitro through modulation of the NGF/TrkA pathway. We also demonstrated that Cblb was a direct target of miR-199a-3p and that Cbl was a direct target of miR-145-5p. Cblb and Cbl gene knockdown resulted in significantly decreased TrkA ubiquitination levels, subsequently activating the NGF/TrkA downstream pathways Akt and Erk. Conversely, overexpression of Cblb and Cbl was associated with significantly increased TrkA ubiquitination level, subsequently inactivating the NGF/TrkA downstream pathways Akt and Erk. Western blot and coimmunoprecipitation assays confirmed the direct interaction between TrkA and Cblb and TrkA and Cbl. In an in vivo experiment, exosomal miR-199a-3p/145-5p was found to upregulate TrkA expression at the lesion site and also promote locomotor function in SCI rats. Conclusions In summary, our study showed that exosomes transferring miR-199a-3p/145-5p into neurons in SCI rats affected TrkA ubiquitination and promoted the NGF/TrkA signaling pathway, indicating that hUC-MSC-derived exosomes may be a promising treatment strategy for SCI.

Effects of cytosine arabinoside on in vivo and in vitro mouse limb development

In Vitro ◽  
1977 ◽  
Vol 13 (7) ◽  
pp. 434-442 ◽  
Author(s):  
Jeanne M. Manson ◽  
Michael L. Dourson ◽  
Carl C. Smith
Keyword(s):  
Cytosine Arabinoside ◽  
Limb Development ◽  
Mouse Limb

Functions of RARs and RXRs in vivo: Genetic dissection of the retinoid signaling pathway

2003 ◽  
Vol 75 (11-12) ◽  
pp. 1709-1732 ◽  
Author(s):  
Manuel Mark ◽  
Pierre Chambon
Keyword(s):  
Signaling Pathway ◽  
Gene Networks ◽  
Es Cells ◽  
Embryonic Stem ◽  
Postnatal Life ◽  
Active Metabolites ◽  
Genetic Studies ◽  
Retinoid Signaling

Retinoids, the active metabolites of vitamin A, regulate complex gene networks involved in vertebrate morphogenesis, growth, cellular differentiation, and homeostasis. They are used for the treatment of skin disorders and as chemopreventive agents for certain cancers. Molecular biology and genetic studies performed during the last 15 years in vitro, using either acellular systems or transfected cells, have shown that retinoid actions are mediated through heterodimers between the 8 major RARα, β, and γ; isoforms and the 6 major RXRα, β and γ isoforms that belong to the nuclear receptor (NR) superfamily, and act as ligand-dependent transcriptional regulators. Furthermore, RXRs not only heterodimerize with RARs, but also with numerous other members of the NR superfamily. As in vitro studies are carried out under nonphysiological conditions, they only indicate what is possible, but not necessarily what is actually occurring in vivo. Therefore, mutations have been introduced by homologous recombination (HR) in F9 embryonal carcinoma (EC) cells, a cell-autonomous system that differentiates in the presence of RA, in order to disrupt RAR and RXR genes and establish their cellular and molecular functions in RA-induced differentiation. However, genetic approaches in the animal should be used to determine the function of retinoid receptors under truly physiological conditions. HR in embryonic stem (ES) cells, has therefore been used to generate null mutations of the various RARs and RXRs in the mouse germline. As reviewed here, the generation of such RAR and RXR germline mutations, combined with pharmacological approaches to block the RA signaling pathway, has provided many valuable insights on the developmental functions of RA receptors. However, due to (i) the complexity in "hormonal" signaling through transduction by the multiple RARs and RXRs, (ii) the functional redundancies (possibly artefactually generated by the mutations) within receptor isotypes belonging to a given gene family, and (iii) in utero or postnatal lethality of certain germline null mutations, these genetic studies through germline mutagenesis have failed to reveal many of the physiological functions of RARs and RXRs, notably in adults. We conclude that spatio-temporally controlled somatic mutations generated in animal models in given cell-types/tissues and at chosen times during pre- and postnatal life, are required to reveal the physiological and pathophysiological functions of the receptor genes involved in the retinoid signaling pathway throughout the life of the mouse.

scholarly journals Cellular retinol binding protein-1 inhibits cancer stemness via upregulating WIF1 to suppress Wnt/β-catenin pathway in hepatocellular carcinoma

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Xiangye Liu ◽  
Wenhua Shan ◽  
Tingting Li ◽  
Xiaoge Gao ◽  
Fanyun Kong ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Retinoic Acid ◽  
Cell Growth ◽  
Signaling Pathway ◽  
Normal Liver ◽  
Retinol Binding Protein ◽  
Cancer Stemness ◽  
Liver Tissues

Abstract Background CRBP-1, a cytosolic chaperone of vitamin A, is identified in a serious number of cancers; however, its biological role in hepatocellular carcinoma (HCC) needs to be further explored. The aim of our present study is to explore the roles and mechanisms of CRBP-1 in regulating liver cancer by using in vitro and in vivo biology approaches. Methods The expression level of CRBP-1 was detected using immunohistochemistry in HCC and matching adjacent non-tumorous liver tissues. Following established stable CRBP-1 overexpressed HCC cell lines, the cell growth and tumorigenicity were investigated both in vitro and in vivo. Intracellular retinoic acid was quantified by ELISA. The relationship between CRBP-1 and WIF1 was validated by using dual luciferase and ChIP analyses. Results The low expression of CRBP-1 was observed in HCC tissues compared to the normal liver tissues, while high CRBP-1 expression correlated with clinicopathological characteristics and increased overall survival in HCC patients. Overexpression of CRBP-1 significantly inhibited cell growth and tumorigenicity both in vitro and in vivo. Moreover, overexpression of CRBP-1 suppressed tumorsphere formation and cancer stemness related genes expression in HCC. Mechanically, CRBP-1 inhibited Wnt/β-catenin signaling pathway to suppress cancer cell stemness of HCC. Furthermore, our results revealed that CRBP-1 could increase the intracellular levels of retinoic acid, which induced the activation of RARs/RXRs leading to the transcriptional expression of WIF1, a secreted antagonist of the Wnt/β-catenin signaling pathway, by physically interacting with the region on WIF1 promoter. Conclusion Our findings reveal that CRBP-1 is a crucial player in the initiation and progression of HCC, which provide a novel independent prognostic biomarker and therapeutic target for the diagnosis and treatment of HCC.

scholarly journals Umbilical Mesenchymal Stem Cell-derived Exosomes Facilitate Spinal Cord Functional Recovery Through the miR-199a-3p/145-5p-mediated NGF/TrkA Signaling Pathway in Rats

2020 ◽  
Author(s):  
Yang Wang ◽  
Xunwei Lai ◽  
Depeng Wu ◽  
Bin Liu ◽  
Nanxiang Wang ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Neurite Outgrowth ◽  
Signaling Pathway ◽  
Direct Interaction ◽  
Lesion Size ◽  
Human Umbilical Cord ◽  
Cord Injury ◽  
Direct Target

Abstract Background Although exosomes, as byproducts of human umbilical cord mesenchymal stem cells (hUC-MSCs), have been demonstrated to be an effective therapy for traumatic spinal cord injury (SCI), their mechanism of action remains unclear. Methods We designed and performed this study to determine whether exosomes attenuate the lesion size of SCI by ameliorating neuronal injury induced by a secondary inflammatory storm and promoting neurite outgrowth. We determined the absolute levels of all exosomal miRNAs and investigated the potential mechanisms of action of miR-199a-3p/145-5p in inducing neurite outgrowth in vivo and in vitro. Results miR-199a-3p/145-5p, which are relatively highly expressed miRNAs in exosomes, promoted PC12 cell differentiation suppressed by lipopolysaccharide (LPS) in vitro through modulation of the NGF/TrkA pathway. We also demonstrated that Cblb was a direct target of miR-199a-3p and that Cbl was a direct target of miR-145-5p. Cblb and Cbl gene knockdown resulted in significantly decreased TrkA ubiquitination levels, subsequently activating the NGF/TrkA downstream pathways Akt and Erk. Conversely, overexpression of Cblb and Cbl was associated with significantly increased TrkA ubiquitination level, subsequently inactivating the NGF/TrkA downstream pathways Akt and Erk. Western blot and coimmunoprecipitation assays confirmed the direct interaction between TrkA and Cblb and TrkA and Cbl. In an in vivo experiment, exosomal miR-199a-3p/145-5p was found to upregulate TrkA expression at the lesion site and also promote locomotor function in SCI rats. Conclusions In summary, our study showed that exosomes transferring miR-199a-3p/145-5p into neurons in SCI rats affected TrkA ubiquitination and promoted the NGF/TrkA signaling pathway, indicating that hUC-MSC-derived exosomes may be a promising treatment strategy for SCI.

scholarly journals Interrogation of gender disparity uncovers androgen receptor as the transcriptional activator for oncogenic miR-125b in gastric cancer

2021 ◽  
Vol 12 (5) ◽  
Author(s):  
Ben Liu ◽  
Meng Zhou ◽  
Xiangchun Li ◽  
Xining Zhang ◽  
Qinghua Wang ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Androgen Receptor ◽  
Signaling Pathway ◽  
Gender Bias ◽  
Gender Disparity ◽  
Gene Set Enrichment Analysis ◽  
Cancer Type ◽  
Female Patients

AbstractThere is a male preponderance in gastric cancer (GC), which suggests a role of androgen and androgen receptor (AR). However, the mechanism of AR signaling in GC especially in female patients remains obscure. We sought to identify the AR signaling pathway that might be related to prognosis and examine the potential clinical utility of the AR antagonist for treatment. Deep learning and gene set enrichment analysis was used to identify potential critical factors associated with gender bias in GC (n = 1390). Gene expression profile analysis was performed to screen differentially expressed genes associated with AR expression in the Tianjin discovery set (n = 90) and TCGA validation set (n = 341). Predictors of survival were identified via lasso regression analyses and validated in the expanded Tianjin cohort (n = 373). In vitro and in vivo experiments were established to determine the drug effect. The GC gender bias was attributable to sex chromosome abnormalities and AR signaling dysregulation. The candidates for AR-related gene sets were screened, and AR combined with miR-125b was associated with poor prognosis, particularly among female patients. AR was confirmed to directly regulate miR-125b expression. AR-miR-125b signaling pathway inhibited apoptosis and promoted proliferation. AR antagonist, bicalutamide, exerted anti-tumor activities and induced apoptosis both in vitro and in vivo, using GC cell lines and female patient-derived xenograft (PDX) model. We have shed light on gender differences by revealing a hormone-regulated oncogenic signaling pathway in GC. Our preclinical studies suggest that AR is a potential therapeutic target for this deadly cancer type, especially in female patients.

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