Left-right side-specific endocrine signaling complements neural pathways to mediate acute asymmetric effects of brain injury.
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ABSTRACT:
SUBMITTER: Lukoyanov N
PROVIDER: S-EPMC8354641 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:There is growing evidence that cancer of the ascending (right-side) colon is different from cancer of the descending (left-side) colon at the molecular level. Using microarray data from 102 right-side colon carcinomas and 95 left-side colon carcinomas we show that different pathways dominate progression to relapse in right-side and left-side colon cancer. Right-side tumors at a high risk for relapse exhibit elevated expression of cell cycle control genes and elevated Wnt signaling. On the other hand, relapse-prone left-side tumors show elevated expression of genes that promote stromal expansion and reduced expression of tumor suppressor genes that initiate Wnt signaling. Single gene prognostic biomarkers are found separately for right-side and left-side disease. In left-side tumors with low expression levels of NADPH oxidase 4 (NOX4) the 5-yr relapse-free survival probability is 0.89 95% CI (0.80-0.99), and in tumors with elevated NOX4 expression the probability is 0.51 95% CI (0.37-0.70). Right-side tumors with elevated expression levels of caudal type homeobox 2 (CDX2) have a 5-yr relapse-free survival probability of 0.88 95% CI (0.80-0.96), and those with low CDX2 expression have a corresponding probability of 0.39 95% CI (0.15-0.78). Both NOX4 and CDX2 are much less prognostic on the opposite sides. This newly identified role of NOX4 in colon cancer is further investigated using the SW620 lymph node metastasis colon adenocarcinoma cell line and RNA interference. We show that NOX4 is expressed in the SW620 cell line and that application of NOX4 siRNA causes a significant reduction in reactive oxidative species production.
| S-EPMC4104680 | biostudies-literature
Project description:BackgroundLeft-right (LR) asymmetry is an essential feature of bilateral animals. Studies in vertebrates show that LR asymmetry formation comprises three major steps: symmetry breaking, asymmetric gene expression, and LR morphogenesis. Although much progress has been made in the first two events, mechanisms underlying asymmetric morphogenesis remain largely unknown due to the complex developmental processes deployed by vertebrate organs.ResultsWe here addressed this question by studying Pitx gene function in the basal chordate amphioxus whose asymmetric organogenesis, unlike that in vertebrates, occurs essentially in situ and does not rely on cell migration. Pitx null mutation in amphioxus causes loss of all left-sided organs and incomplete ectopic formation of all right-sided organs on the left side, whereas Pitx partial loss-of-function leads to milder phenotypes with only some LR organs lost or ectopically formed. At the N1 to N3 stages, Pitx expression is gradually expanded from the dorsal anterior domain to surrounding regions. This leads to activation of genes like Lhx3 and/or Prop1 and Pit, which are essential for left-side organs, and downregulation of genes like Hex and/or Nkx2.1 and FoxE4, which are required for right-side organs to form ectopically on the left side. In Pitx mutants, the left-side expressed genes are not activated, while the right-side genes fail to decrease expression on the left side. In contrast, in embryos overexpressing Pitx genes, the left-side genes are induced ectopically on the right side, and the right-side genes are inhibited. Several Pitx binding sites are identified in the upstream sequences of the left-side and right-side genes which are essential for activation of the former and repression of the latter by Pitx.ConclusionsOur results demonstrate that (1) Pitx is a major (although not the only) determinant of asymmetric morphogenesis in amphioxus, (2) the development of different LR organs have distinct requirements for Pitx activity, and (3) Pitx controls amphioxus LR morphogenesis probably through inducing left-side organs and inhibiting right-side organs directly. These findings show much more dependence of LR organogenesis on Pitx in amphioxus than in vertebrates. They also provide insight into the molecular developmental mechanism of some vertebrate LR organs like the lungs and atria, since they show a right-isomerism phenotype in Pitx2 knockout mice like right-sided organs in Pitx mutant amphioxus. Our results also explain why some organs like the adenohypophysis are asymmetrically located in amphioxus but symmetrically positioned in vertebrates.
| S-EPMC8377849 | biostudies-literature
Project description:The nodal gene is expressed on the left side of developing mouse embryos and is implicated in left/right (L-R) axis formation. The transcriptional regulatory regions of nodal have now been investigated by transgenic analysis. A node-specific enhancer was detected in the upstream region (-9.5 to -8.7 kb) of the gene. Intron 1 was also shown to contain a left side-specific enhancer (ASE) that was able to direct transgene expression in the lateral plate mesoderm and prospective floor plate on the left side. A 3. 5-kb region of nodal that contained ASE responded to mutations in iv, inv, and lefty-1, all genes that act upstream of nodal. The same 3. 5- kb region also directed expression in the epiblast and visceral endoderm at earlier stages of development. Characterization of deletion constructs delineated ASE to a 340-bp region that was both essential and sufficient for asymmetric expression of nodal. Several sequence motifs were found to be conserved between the nodal ASE and the lefty-2 ASE, some of which appeared to be essential for nodal ASE activity. These results suggest that similar transcriptional mechanisms underlie the asymmetric expression of nodal and of lefty-2 as well as the earlier expression of nodal in the epiblast and endoderm.
| S-EPMC316797 | biostudies-literature
Project description:GoalsWe aim to draw a conclusion which type of hepatectomy could be the priority for hilar cholangiocarcinoma patients.BackgroundSurgery is established as only potentially curative treatment for hilar cholangiocarcinoma. However, whether hepatectomy should be preferred to the left-side hepatectomy, which includes left hemihepatectomy, extended left hemihepatectomy, and left trisectionectomy, or right-side hepatectomy, which represents right hemihepatectomy, extended right hemihepatectomy, and right trisectionectomy, is debated. In this meta-analysis, we evaluated and compared the efficacy and safety of left-side hepatectomy and right-side hepatectomy in patients with hilar cholangiocarcinoma.StudyWe systematically retrieved the MEDLINE, PubMed, and Cochrane library and related bibliography up to February 2020. The primary outcome is overall survival, and the secondary outcome includes 1-, 3-, and 5-year survival rates, morbidity, mortality, R0 resection rate, and operation time. Based on heterogeneity, fixed-effects model or random-effects models were established through meta-analysis.ResultsEleven studies (11 cohort studies, totally 1031 patients) were involved in this study. The overall survival of patients who underwent left-side hepatectomy was comparable to that of patients who underwent right-side hepatectomy (hazard ratio, 1.27 [95% confidence interval, 0.98-1.63]). And there was no significant difference observed in 1-year (relative risk, 1.01 [95% CI, 0.89-1.15]), 3-year (relative risk, 0.94 [95% confidence interval, 0.80-1.11]), and 5-year survival (relative risk, 0.82 [95% confidence interval, 0.67-1.01]) rates between the left-side hepatectomy group and the right-side hepatectomy group. Comparing with the right-side hepatectomy cluster, the hilar cholangiocarcinoma patients in the left-side hepatectomy cluster presented better overall postoperative morbidity (relative risk, 0.82 [95% confidence interval, 0.71-0.96]) and major postoperative morbidity (relative risk, 0.73 [95% confidence interval, 0.56-0.95]). The post-hepatectomy liver failure rate (relative risk, 0.22 [95% confidence interval, 0.09-0.56]) and procedure-related mortality (relative risk, 0.41 [95% confidence interval, 0.23-0.70]) in the left-side hepatectomy group were better than those of the right-side hepatectomy group. Besides, the R0 resection rate was similar between the left-side hepatectomy group and the right-side hepatectomy group (relative risk, 0.95 [95% confidence interval, 0.87-1.03]). And the operation time for the left-side hepatectomy was significantly longer than that for the right-side hepatectomy (mean difference, 38.68 [95% confidence interval, 7.41-69.95]).ConclusionThrough meta-analysis, we explored the comparable long-term outcomes and better short-term outcomes in the left-side hepatectomy group as is compared to the right-side hepatectomy group of hilar cholangiocarcinoma patients. In this study, the evidence obtained might indicate that the choice of left-side hepatectomy or right-side hepatectomy depends on the site of hilar cholangiocarcinoma in every patient.
| S-EPMC8037893 | biostudies-literature
Project description:Polarized epithelial morphogenesis is an essential process in animal development. While this process is mostly attributed to directional cell intercalation, it can also be induced by other mechanisms. Using live-imaging analysis and a three-dimensional vertex model, we identified 'cell sliding,' a novel mechanism driving epithelial morphogenesis, in which cells directionally change their position relative to their subjacent (posterior) neighbors by sliding in one direction. In Drosophila embryonic hindgut, an initial left-right (LR) asymmetry of the cell shape (cell chirality in three dimensions), which occurs intrinsically before tissue deformation, is converted through LR asymmetric cell sliding into a directional axial twisting of the epithelial tube. In a Drosophila inversion mutant showing inverted cell chirality and hindgut rotation, cell sliding occurs in the opposite direction to that in wild-type. Unlike directional cell intercalation, cell sliding does not require junctional remodeling. Cell sliding may also be involved in other cases of LR-polarized epithelial morphogenesis.
| S-EPMC5997448 | biostudies-literature
Project description:The functional organization of left and right hemispheres is different, and hemispheric asymmetries are thought to underlie variations in brain function across individuals. In this study, we assess how differences between hemispheres are reflected in Asymmetric Functional Connectivity (AFC), which provides a full description of how the brain's connectivity structure during resting state differs from that of the same brain mirrored over the longitudinal fissure. In addition, we assess how AFC varies across subjects. Data were provided by the Human Connectome Project, including 423 resting state and combined language task fMRI data sets, and the pattern of AFC was established for all subjects. While we could quantify the symmetry of brain connectivity at 95%, significant asymmetries were observed, consisting foremost of: (1) higher correlations between language areas in the left hemisphere than between their right hemisphere homologues. (2) Higher correlations between language homologue areas in the right hemisphere and left default mode network, than between language areas in the left hemisphere and the default mode network in the right hemisphere. The extent to which subjects exhibited this pattern correlated with language lateralization and handedness. Further exploration in intersubject variation in AFC revealed several additional patterns, one involving entire hemispheres, and another correlations with limbic areas. These results show that language is an important, but not only determinant of AFC. The additional patterns of AFC require further research to be linked to specific asymmetric neuronal states or events.
| S-EPMC5884915 | biostudies-literature
Project description:BackgroundNodal is an important determinant of the left-right (LR) body axis in bilaterians, specifying the right side in protostomes and non-chordate deuterostomes as opposed to the left side in chordates. Amphioxus represents an early-branching chordate group, rendering it especially useful for studying the character states that predate the origin of vertebrates. However, its anatomy, involving offset arrangement of axial structures, marked asymmetry of the oropharyngeal region, and, most notably, a mouth positioned on the left side, contrasts with the symmetric arrangement of the corresponding regions in other chordates.ResultsWe show that the Nodal signaling pathway acts to specify the LR axis in the cephalochordate amphioxus in a similar way as in vertebrates. At early neurula stages, Nodal switches from initial bilateral to the left-sided expression and subsequently specifies the left embryonic side. Perturbation of Nodal signaling with small chemical inhibitors (SB505124 and SB431542) alters expression of other members of the pathway and of left/right-sided, organ-specific genes. Upon inhibition, larvae display loss of the innate alternation of both somites and axons of peripheral nerves and loss of left-sided pharyngeal structures, such as the mouth, the preoral pit, and the duct of the club-shaped gland. Concomitantly, the left side displays ectopic expression of otherwise right-sided genes, and the larvae exhibit bilaterally symmetrical morphology, with duplicated endostyle and club-shaped gland structures.ConclusionsWe demonstrate that Nodal signaling is necessary for establishing the LR embryonic axis and for developing profound asymmetry in amphioxus. Our data suggest that initial symmetry breaking in amphioxus and propagation of the pathway on the left side correspond with the situation in vertebrates. However, the organs that become targets of the pathway differ between amphioxus and vertebrates, which may explain the pronounced asymmetry of its oropharyngeal and axial structures and the left-sided position of the mouth.
| S-EPMC4423147 | biostudies-literature
Project description:BackgroundAlthough left-right asymmetries are common features of nervous systems, their developmental bases are largely unknown. In the zebrafish epithalamus, dorsal habenular neurons adopt medial (dHbm) and lateral (dHbl) subnuclear character at very different frequencies on the left and right sides. The left-sided parapineal promotes the elaboration of dHbl character in the left habenula, albeit by an unknown mechanism. Likewise, the genetic pathways acting within habenular neurons to control their asymmetric differentiated character are unknown.ResultsIn a forward genetic screen for mutations that result in loss of habenular asymmetry, we identified two mutant alleles of tcf7l2, a gene that encodes a transcriptional regulator of Wnt signaling. In tcf7l2 mutants, most neurons on both sides differentiate with dHbl identity. Consequently, the habenulae develop symmetrically, with both sides adopting a pronounced leftward character. Tcf7l2 acts cell automously in nascent equipotential neurons, and on the right side, it promotes dHbm and suppresses dHbl differentiation. On the left, the parapineal prevents this Tcf7l2-dependent process, thereby promoting dHbl differentiation.ConclusionsTcf7l2 is essential for lateralized fate selection by habenular neurons that can differentiate along two alternative pathways, thereby leading to major neural circuit asymmetries.
| S-EPMC4194317 | biostudies-literature
Project description:BackgroundRight-sided colorectal cancer (CRC) has worse survival than does left-sided CRC. The objective of this study was to further assess the impact of right-side location on survival and the role of the extent of lymphadenectomy.MethodsAll CRCs diagnosed between 2000 and 2012 in Emilia-Romagna Region, Italy, were included. Data for stage, grade, histology, screening history, and number of removed lymph nodes (LN) were collected. Multivariable Cox regression models were used to estimate hazard ratios (HR), with relative 95% confidence intervals (95%CI), of right vs. left colon and of removing < 12, 12-21 or > 21 lymph nodes by cancer site.ResultsDuring the study period, 29,358 patients were registered (8828 right colon, 18,852 left colon, 1678 transverse). Patients with right cancer were more often older, females, with advanced stage and high grade, and higher number of removed LNs. Five-year survival was lower in the right than in the left colon (55.2% vs 59.7%). In multivariable analysis, right colon showed a lower survival when adjusting for age, sex, and screening status (HR 1.12, 95%CI 1.04-1.21). Stratification by number of lymph nodes removed (12-21 or > 21) was associated with better survival in right colon (HR 0.54, 95%CI 0.40-0.72 and HR 0.40, 95%CI 0.30-0.55, respectively) compared to left colon (HR 0.89, 95%CI 0.76-1.06 and HR 0.83, 95%CI 0.69-1.01, respectively).ConclusionsThis study confirms that right CRC has worse survival; the association is not due to screening status. An adequate removal of lymph nodes is associated with better survival, although the direction of the association in terms of causal links is not clear.
| S-EPMC8117551 | biostudies-literature
Project description:Structural birth defects are the leading cause of infant mortality in the United States. Many of these defects are associated with abnormal anatomical left-right asymmetry. Despite the importance of orienting organs along the left-right (L-R) axis during development, very little is known about the molecular events that control this process. To elucidate the genetic mechanisms that shape the L-R asymmetry of individual organs, we sought to identify genes that are expressed in L-R asymmetric patterns during organ development. To accomplish this goal, we took advantage of the exceptionally large Budgett’s frog (Lepidobatrachus laevis) embryo to profile gene expression by RNA-seq in the left versus right halves of the developing stomach. Using this data, we have constructed a de novo Lepidobatrachus transcriptome and identified ~26,000 unique transcripts with human homology based on reciprocal BLAST analyses. Over 300 transcripts were L-R asymmetrically expressed within the stomach. Among these candidates are some of the few genes already known to play a role in L-R asymmetric development, validating our strategy for L-R gene discovery.
2023-05-26 | GSE99817 | GEO