scholarly journals RASA1-driven cellular export of collagen IV is required for the development of lymphovenous and venous valves in mice

Development ◽  
2020 ◽  
Vol 147 (23) ◽  
pp. dev192351
Author(s):  
Di Chen ◽  
Xin Geng ◽  
Philip E. Lapinski ◽  
Michael J. Davis ◽  
R. Sathish Srinivasan ◽  
...  
Keyword(s):  
Mapk Signaling ◽  
Collagen Iv ◽  
Venous Hypertension ◽  
Negative Regulator ◽  
Ras Signaling ◽  
Venous Valves ◽  
Adult Mice ◽  
Basement Membrane Protein ◽  
Inactive Form ◽  
Mapk Inhibitors

ABSTRACTRASA1, a negative regulator of Ras-MAPK signaling, is essential for the development and maintenance of lymphatic vessel valves. However, whether RASA1 is required for the development and maintenance of lymphovenous valves (LVV) and venous valves (VV) is unknown. In this study, we show that induced disruption of Rasa1 in mouse embryos did not affect initial specification of LVV or central VV, but did affect their continued development. Similarly, a switch to expression of a catalytically inactive form of RASA1 resulted in impaired LVV and VV development. Blocked development of LVV was associated with accumulation of the basement membrane protein, collagen IV, in LVV-forming endothelial cells (EC), and could be partially or completely rescued by MAPK inhibitors and drugs that promote collagen IV folding. Disruption of Rasa1 in adult mice resulted in venous hypertension and impaired VV function that was associated with loss of EC from VV leaflets. In conclusion, RASA1 functions as a negative regulator of Ras signaling in EC that is necessary for EC export of collagen IV, thus permitting the development of LVV and the development and maintenance of VV.

scholarly journals RASA1-driven cellular export of collagen IV is required for the development of lymphovenous and venous valves in mice

2020 ◽  
Author(s):  
Di Chen ◽  
Xin Geng ◽  
Philip E. Lapinski ◽  
Michael J. Davis ◽  
R. Sathish Srinivasan ◽  
...  
Keyword(s):  
Mapk Signaling ◽  
Collagen Iv ◽  
Venous Hypertension ◽  
Negative Regulator ◽  
Mitogen Activated Protein Kinase ◽  
Ras Signaling ◽  
Venous Valves ◽  
Adult Mice ◽  
Mitogen Activated Protein ◽  
Mapk Inhibitors

RASA1, a negative regulator of the Ras-mitogen-activated protein kinase (MAPK) signaling pathway, is essential for the development and maintenance of lymphatic vessel (LV) valves. However, whether RASA1 is required for the development and maintenance of lymphovenous valves (LVV) and venous valves (VV) is unknown. In this study we show that induced endothelial cell (EC)-specific disruption of Rasa1 in mid-gestation mouse embryos did not affect initial specification of LVV or central VV but did affect their continued development. Similarly, switch to expression of a catalytically inactive form of RASA1 resulted in impaired LVV and VV development. Blocked development of LVV in RASA1-deficient embryos was associated with accumulation of the basement membrane protein, collagen IV, in LVV-forming EC and could be partially or completely rescued by MAPK inhibitors and drugs that promote collagen IV folding. Disruption of Rasa1 in adult mice resulted in venous hypertension and impaired VV function that was associated with loss of EC from VV leaflets. In conclusion, RASA1 functions as a negative regulator of Ras signaling in EC that is necessary for EC export of collagen IV, thus permitting the development of LVV and the development and maintenance of VV.

scholarly journals Loss of Capicua alters early T cell development and predisposes mice to T cell lymphoblastic leukemia/lymphoma

2018 ◽  
Vol 115 (7) ◽  
pp. E1511-E1519 ◽  
Author(s):  
Qiumin Tan ◽  
Lorenzo Brunetti ◽  
Maxime W. C. Rousseaux ◽  
Hsiang-Chih Lu ◽  
Ying-Wooi Wan ◽  
...  
Keyword(s):  
T Cell ◽  
Tumor Suppressor ◽  
Neurological Diseases ◽  
Lymphoblastic Leukemia ◽  
Mapk Signaling ◽  
Spinocerebellar Ataxia Type ◽  
Ras Signaling ◽  
Embryonic Patterning ◽  
Lymphoid Malignancies ◽  
Adult Mice

Capicua (CIC) regulates a transcriptional network downstream of the RAS/MAPK signaling cascade. In Drosophila, CIC is important for many developmental processes, including embryonic patterning and specification of wing veins. In humans, CIC has been implicated in neurological diseases, including spinocerebellar ataxia type 1 (SCA1) and a neurodevelopmental syndrome. Additionally, we and others have reported mutations in CIC in several cancers. However, whether CIC is a tumor suppressor remains to be formally tested. In this study, we found that deletion of Cic in adult mice causes T cell acute lymphoblastic leukemia/lymphoma (T-ALL). Using hematopoietic-specific deletion and bone marrow transplantation studies, we show that loss of Cic from hematopoietic cells is sufficient to drive T-ALL. Cic-null tumors show up-regulation of the KRAS pathway as well as activation of the NOTCH1 and MYC transcriptional programs. In sum, we demonstrate that loss of CIC causes T-ALL, establishing it as a tumor suppressor for lymphoid malignancies. Moreover, we show that mouse models lacking CIC in the hematopoietic system are robust models for studying the role of RAS signaling as well as NOTCH1 and MYC transcriptional programs in T-ALL.

scholarly journals Relation between extent of myostatin depletion and muscle growth in mature mice

2009 ◽  
Vol 297 (4) ◽  
pp. E935-E940 ◽  
Author(s):  
Stephen Welle ◽  
Kerri Burgess ◽  
Charles A. Thornton ◽  
Rabi Tawil
Keyword(s):  
Muscle Mass ◽  
Normal Level ◽  
Muscle Growth ◽  
Mapk Signaling ◽  
Negative Regulator ◽  
Adult Mice ◽  
Fiber Size ◽  
Myonuclear Domain ◽  
Potential Strategy ◽  
Mapk Signaling Pathways

Myostatin is a negative regulator of muscle growth and fiber size. Changes in myostatin expression might contribute to changes in muscle mass associated with various conditions, and reducing the amount of active myostatin is a potential strategy for preventing or reversing muscle atrophy. The present study was done to determine the extent to which myostatin levels must decline to induce growth of mature muscles. Myostatin expression was reduced by activating Cre recombinase in adult mice with floxed myostatin genes. The duration of Cre activation varied from 1 to 6 wk, and the residual myostatin mRNA expression after Cre activation varied from 3 to 63% of the normal level. Promyostatin levels declined in parallel with myostatin mRNA. There was no increase in muscle mass over the 3 mo following Cre activation if residual myostatin expression was ≥40% of normal. In mice with <40% of normal myostatin expression, muscle mass increased in proportion to the extent of myostatin depletion. In mice with ≤10% of normal myostatin expression, muscle mass increased ∼25%. Myostatin depletion increased myonuclear domain volumes and the ratio of RNA to myonuclei probably by enhancing DNA transcription rather than by inhibiting RNA decay. There was no evidence that maintenance of the hypertrophy during chronic myostatin deficiency requires altered activity of Akt/mTOR or p38 MAPK signaling pathways. These data suggest that anabolic therapies based on reducing the concentration of active myostatin will be effective only if a very large proportion of the myostatin is removed or inactivated.

scholarly journals Distinctive epigenomic alterations in NF1-deficient cutaneous and plexiform neurofibromas drive differential MKK/p38 signaling

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Jamie L. Grit ◽  
Benjamin K. Johnson ◽  
Patrick S. Dischinger ◽  
Curt J. Essenburg ◽  
Marie Adams ◽  
...  
Keyword(s):  
Conformational Changes ◽  
Transcriptome Profiling ◽  
Neurofibromatosis Type ◽  
Mapk Signaling ◽  
Ras Signaling ◽  
Methylation Array ◽  
Clinical Behavior ◽  
Plexiform Neurofibromas ◽  
Cellular Processes ◽  
Peripheral Nerve Sheath Tumors

AbstractBenign peripheral nerve sheath tumors are the clinical hallmark of Neurofibromatosis Type 1. They account for substantial morbidity and mortality in NF1. Cutaneous (CNF) and plexiform neurofibromas (PNF) share nearly identical histology, but maintain different growth rates and risk of malignant conversion. The reasons for this disparate clinical behavior are not well explained by recent genome or transcriptome profiling studies. We hypothesized that CNFs and PNFs are epigenetically distinct tumor types that exhibit differential signaling due to genome-wide and site-specific methylation events. We interrogated the methylation profiles of 45 CNFs and 17 PNFs from NF1 subjects with the Illumina EPIC 850K methylation array. Based on these profiles, we confirm that CNFs and PNFs are epigenetically distinct tumors with broad differences in higher-order chromatin states and specific methylation events altering genes involved in key biological and cellular processes, such as inflammation, RAS/MAPK signaling, actin cytoskeleton rearrangement, and oxytocin signaling. Based on our identification of two separate DMRs associated with alternative leading exons in MAP2K3, we demonstrate differential RAS/MKK3/p38 signaling between CNFs and PNFs. Epigenetic reinforcement of RAS/MKK/p38 was a defining characteristic of CNFs leading to pro-inflammatory signaling and chromatin conformational changes, whereas PNFs signaled predominantly through RAS/MEK. Tumor size also correlated with specific CpG methylation events. Taken together, these findings confirm that NF1 deficiency influences the epigenetic regulation of RAS signaling fates, accounting for observed differences in CNF and PNF clinical behavior. The extension of these findings is that CNFs may respond differently than PNFs to RAS-targeted therapeutics raising the possibility of targeting p38-mediated inflammation for CNF treatment.

scholarly journals Ovary-derived circular RNAs profile analysis during the onset of puberty in gilts

BMC Genomics ◽  
2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Xiangchun Pan ◽  
Wentao Gong ◽  
Yingting He ◽  
Nian Li ◽  
Hao Zhang ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Signaling Pathway ◽  
Gene Networks ◽  
Profile Analysis ◽  
Mirna Gene ◽  
Mapk Signaling ◽  
Circular Rnas ◽  
Ras Signaling ◽  
Female Reproduction ◽  
Non Coding Rna

Abstract Background In mammals, the ovary is the essential system of female reproduction for the onset of puberty, and the abnormal puberty has negative outcomes on health. CircRNA is a non-coding RNA produced by non-canonical alternative splicing (AS). Several studies have reported that circRNA is involved in the gene regulation and plays an important role in some human diseases. However, the contribution of circRNA has received little known within the onset of puberty in ovary. Results Here, the profiles of ovarian circRNAs across pre-, in- and post-pubertal stages were established by RNA-sEq. In total, 972 circRNAs were identified, including 631 stage-specific circRNAs and 8 tissue-specific circRNAs. The biological functions of parental genes of circRNAs were enriched in steroid biosynthesis, autophagy-animal, MAPK signaling pathway, progesterone-mediated oocyte maturation and ras signaling pathway. Moreover, 5 circRNAs derived from 4 puberty-related genes (ESR1, JAK2, NF1 and ARNT) were found in this study. The A3SS events were the most alternative splicing, but IR events were likely to be arose in post-pubertal ovaries. Besides, the circRNA-miRNA-gene networks were explored for 10 differentially expressed circRNAs. Furthermore, the head-to-tail exon as well as the expressions of 10 circRNAs were validated by the divergent RT-qPCR and sanger sequencing. Conclusions In summary, the profiles of ovarian circRNAs were provided during pubertal transition in gilts, and these results provided useful information for the investigation on the onset of puberty at the ovarian-circRNAs-level in mammals.

scholarly journals The Caenorhabditis elegans locus lin-15, a negative regulator of a tyrosine kinase signaling pathway, encodes two different proteins.

Genetics ◽  
1994 ◽  
Vol 137 (4) ◽  
pp. 987-997 ◽  
Author(s):  
S G Clark ◽  
X Lu ◽  
H R Horvitz
Keyword(s):  
Caenorhabditis Elegans ◽  
Tyrosine Kinase ◽  
Signaling Pathway ◽  
Genomic Region ◽  
Negative Regulator ◽  
Ras Signaling ◽  
Intercellular Signaling ◽  
Tyrosine Kinase Signaling ◽  
Genomic Regions ◽  
Mrna Precursor

Abstract The Caenorhabditis elegans locus lin-15 negatively regulates an intercellular signaling process that induces formation of the hermaphrodite vulva. The lin-15 locus controls two separate genetic activities. Mutants that lack both activities have multiple, ectopic pseudo-vulvae resulting from the overproduction of vulval cells, whereas mutants defective in only one lin-15 activity appear wild-type. lin-15 acts non-cell-autonomously to prevent the activation of a receptor tyrosine kinase/ras signaling pathway. We report here the molecular characterization of the lin-15 locus. The two lin-15 activities are encoded by contiguous genomic regions and by two distinct, non-overlapping transcripts that may be processed from a single mRNA precursor by trans-splicing. Based on the DNA sequence, the 719- and 1,440-amino acid lin-15 proteins are not similar to each other or to known proteins. lin-15 multivulva mutants, which are defective in both lin-15 activities, contain deletions and insertions that affect the lin-15 genomic region.

NrasQ61R/+ and Kras-/- cooperate to downregulate Rasgrp1 and promote lympho-myeloid leukemia in early T-cell precursors

Blood ◽  
2021 ◽  
Author(s):  
Zhi Wen ◽  
Grant Yun ◽  
Alexander Hebert ◽  
Guangyao Kong ◽  
Erik A. Ranheim ◽  
...  
Keyword(s):  
T Cell ◽  
Lymphoblastic Leukemia ◽  
Transcript Level ◽  
Negative Regulator ◽  
Erk Signaling ◽  
Ras Signaling ◽  
Nucleotide Exchange ◽  
Promote Cell Proliferation ◽  
Oncogenic Ras ◽  
Molecular Features

Early T cell precursor acute lymphoblastic leukemia (ETP-ALL) is an aggressive subtype of T-ALL. Although genetic mutations hyperactivating cytokine receptor/Ras signaling are prevalent in ETP-ALL, it remains unknown how activated Ras signaling contributes to ETP-ALL. Here, we find that in addition to the frequent oncogenic RAS mutations, wild-type (WT) KRAS transcript level was significantly downregulated in human ETP-ALL cells. Similarly, loss of WT Kras in NrasQ61R/+ mice promoted hyperactivation of ERK signaling, thymocyte hyperproliferation, and expansion of ETP compartment. Kras-/-;NrasQ61R/+ mice developed early onset of T-cell malignancy that recapitulates many biological and molecular features of human ETP-ALL. Mechanistically, RNA-Seq analysis and quantitative proteomics study identified that Rasgrp1, a Ras guanine nucleotide exchange factor, was greatly downregulated in mouse and human ETP-ALL. Unexpectedly, hyperactivated Nras/ERK signaling suppressed Rasgrp1 expression and reduced Rasgrp1 level led to increased ERK signaling, thereby establishing a positive feedback loop to augment Nras/ERK signaling and promote cell proliferation. Corroborating our cell line data, Rasgrp1 haploinsufficiency induced Rasgrp1 downregulation, increased pERK level, and ETP expansion in NrasQ61R/+ mice. Our study identifies Rasgrp1 as a negative regulator of Ras/ERK signaling in oncogenic Nras-driven ETP-like leukemia.

Analysis of MicroRNA Transcriptomes Insights into the miR-148a-3p Inducer of Rumen Development in Goats

2020 ◽  
Author(s):  
Tao Zhong ◽  
Cheng Wang ◽  
Jiangtao Hu ◽  
Xiaoyong Chen ◽  
Lili Niu ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Target Genes ◽  
Genetic Regulation ◽  
Mapk Signaling ◽  
Regulation Mechanism ◽  
Ras Signaling ◽  
Genome Wide ◽  
A Genome ◽  
Differentially Expressed Mirnas ◽  
And Function

Abstract Background: Rumen is an important digestive organ of ruminant. From fetal to adult stage, the morphology, structure and function of rumen have changed significantly. But the intrinsic genetic regulation is still limited. We previously reported a genome-wide expression profile of miRNAs in prenatal goat rumens. In the present study, we rejoined analyzed the transcriptomes of rumen miRNAs during prenatal (E60 and E135) and postnatal (D30 and D150) stages.Results: A total of 66 differentially expressed miRNAs (DEMs) were identified in the rumen tissues from D30 and D150 goats. Of these, 17 DEMs were consistently highly expressed in the rumens at the preweaning stages (E60, E135 and D30), while down-regulated at D150. Noteworthy, annotation analysis revealed that the target genes regulated by the DEMs were mainly enriched in MAPK signaling pathway, Jak-STAT signaling pathway and Ras signaling pathway. Interestingly, the expression of miR-148a-3p was significantly high in the embryonic stage and down-regulated at D150. The potential binding sites between miR-148a-3p and QKI were predicted by the TargetScan and verified by the dual luciferase report assay. The co-localization of miR-148a-3p and QKI was observed not in intestinal tracts but in rumen tissues by in situ hybridization. Moreover, the expression of miR-148a-3p in the epithelium was significantly higher than that in the other layers, suggesting that miR-148a-3p involve in the development of rumen epithelial cells by targeting QKI. Subsequently, miR-148a-3p inhibitor was found to induce the proliferation of GES-1 cells.Conclusions: Taken together, these results identified the DEMs involved in the development of rumen and provided an insight into the regulation mechanism of goat rumens during development.

scholarly journals Peroxidasin-mediated bromine enrichment of basement membranes

2020 ◽  
Vol 117 (27) ◽  
pp. 15827-15836
Author(s):  
Cuiwen He ◽  
Wenxin Song ◽  
Thomas A. Weston ◽  
Caitlyn Tran ◽  
Ira Kurtz ◽  
...  
Keyword(s):  
Basement Membrane ◽  
Knockout Mice ◽  
Structural Integrity ◽  
Secondary Ion Mass Spectrometry ◽  
Human Kidney ◽  
Collagen Iv ◽  
Basement Membranes ◽  
Basement Membrane Protein ◽  
Mammalian Tissues ◽  
Cross Links

Bromine and peroxidasin (an extracellular peroxidase) are essential for generating sulfilimine cross-links between a methionine and a hydroxylysine within collagen IV, a basement membrane protein. The sulfilimine cross-links increase the structural integrity of basement membranes. The formation of sulfilimine cross-links depends on the ability of peroxidasin to use bromide and hydrogen peroxide substrates to produce hypobromous acid (HOBr). Once a sulfilimine cross-link is created, bromide is released into the extracellular space and becomes available for reutilization. Whether the HOBr generated by peroxidasin is used very selectively for creating sulfilimine cross-links or whether it also causes oxidative damage to bystander molecules (e.g., generating bromotyrosine residues in basement membrane proteins) is unclear. To examine this issue, we used nanoscale secondary ion mass spectrometry (NanoSIMS) imaging to define the distribution of bromine in mammalian tissues. We observed striking enrichment of bromine (79Br,81Br) in basement membranes of normal human and mouse kidneys. In peroxidasin knockout mice, bromine enrichment of basement membranes of kidneys was reduced by ∼85%. Proteomic studies revealed bromination of tyrosine-1485 in the NC1 domain of α2 collagen IV from kidneys of wild-type mice; the same tyrosine was brominated in collagen IV from human kidney. Bromination of tyrosine-1485 was reduced by >90% in kidneys of peroxidasin knockout mice. Thus, in addition to promoting sulfilimine cross-links in collagen IV, peroxidasin can also brominate a bystander tyrosine. Also, the fact that bromine enrichment is largely confined to basement membranes implies that peroxidasin activity is largely restricted to basement membranes in mammalian tissues.

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