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The integrator complex subunit 6 (Ints6) confines the dorsal organizer in vertebrate embryogenesis.

ABSTRACT: Dorsoventral patterning of the embryonic axis relies upon the mutual antagonism of competing signaling pathways to establish a balance between ventralizing BMP signaling and dorsal cell fate specification mediated by the organizer. In zebrafish, the initial embryo-wide domain of BMP signaling is refined into a morphogenetic gradient following activation dorsally of a maternal Wnt pathway. The accumulation of ?-catenin in nuclei on the dorsal side of the embryo then leads to repression of BMP signaling dorsally and the induction of dorsal cell fates mediated by Nodal and FGF signaling. A separate Wnt pathway operates zygotically via Wnt8a to limit dorsal cell fate specification and maintain the expression of ventralizing genes in ventrolateral domains. We have isolated a recessive dorsalizing maternal-effect mutation disrupting the gene encoding Integrator Complex Subunit 6 (Ints6). Due to widespread de-repression of dorsal organizer genes, embryos from mutant mothers fail to maintain expression of BMP ligands, fail to fully express vox and ved, two mediators of Wnt8a, display delayed cell movements during gastrulation, and severe dorsalization. Consistent with radial dorsalization, affected embryos display multiple independent axial domains along with ectopic dorsal forerunner cells. Limiting Nodal signaling or restoring BMP signaling restores wild-type patterning to affected embryos. Our results are consistent with a novel role for Ints6 in restricting the vertebrate organizer to a dorsal domain in embryonic patterning.

SUBMITTER: Kapp LD

PROVIDER: S-EPMC3814294 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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The integrator complex subunit 6 (Ints6) confines the dorsal organizer in vertebrate embryogenesis.

Kapp Lee D LD Abrams Elliott W EW Marlow Florence L FL Mullins Mary C MC

PLoS genetics 20131031 10

Dorsoventral patterning of the embryonic axis relies upon the mutual antagonism of competing signaling pathways to establish a balance between ventralizing BMP signaling and dorsal cell fate specification mediated by the organizer. In zebrafish, the initial embryo-wide domain of BMP signaling is refined into a morphogenetic gradient following activation dorsally of a maternal Wnt pathway. The accumulation of β-catenin in nuclei on the dorsal side of the embryo then leads to repression of BMP sig ...[more]

PMID: 24204286

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Project description:BackgroundIntegrator complex subunit 6 (INTS6) was found to play a tumour suppressing role in certain types of solid tumours. In this study, we wanted to determine the expression level of INTS6 in hepatocellular carcinoma (HCC) and evaluate its clinical characteristics and mechanisms in HCC patients (Lui and Lu, European Journal of Cancer, 51:S94, 2015).MethodsFirst, we used a microarray analysis to explore the mRNA expression levels in HCC and paired normal liver tissues; second, we used qRT-PCR to measure the INTS6 mRNA levels in a cohort of 50 HCC tissues and adjacent normal liver tissues; third, we used Western blot analyses to detect the INTS6 protein levels in 20 paired HCC and normal liver tissues; fourth, we used immunohistochemistry to determine the INTS6 expression levels in 70 archived paraffin-embedded HCC samples. Finally, we investigated the suppressive function of INTS6 in the Wnt pathway.ResultsHerein, according to the microarray data analysis, the expression levels of INTS6 were dramatically down-regulated in HCC tissues vs. those in normal liver tissues (p<0.05). qRT-PCR and Western blot analyses showed that the INTS6 mRNA and protein expression was significantly down-regulated in tumour tissues compared to the adjacent normal liver tissues (p<0.05). Immunohistochemical assays revealed that decreased INTS6 expression was present in 62.9% (44/70) of HCC patients. Correlation analyses showed that INTS6 expression was significantly correlated with serum alpha-fetoprotein levels (AFP, p =0.004), pathology grade (p =0.005), and tumour recurrence (p =0.04). Kaplan-Meier analysis revealed that patients with low INTS6 expression levels had shorter overall and disease-free survival rates than patients with high INTS6 expression levels (p =0.001 and p =0.001). Multivariate regression analysis indicated that INTS6 was an independent predictor of overall survival and disease-free survival rates. Mechanistically, INTS6 increased WIF-1 expression and then inhibited the Wnt/β-catenin signalling pathway.ConclusionThe results of our study show that down-regulated INTS6 expression is associated with a poorer prognosis in HCC patients. This newly identified INTS6/WIF-1 axis indicates the molecular mechanism of HCC and may represent a therapeutic target in HCC patients.

Project description:This study presents statistical analyses of gene expression during all 40 developmental stages in the teleost Fundulus heteroclitus using four biological replicates per stage. Patterns of gene expression for 7,000 genes appear to be important as they recapitulate developmental timing. Among the 45% of genes with significant expression differences between pairs of temporally adjacent stages, significant differences in gene expression vary from as few as five to more than 660. Five adjacent stages have disproportionately more significant changes in gene expression (>200 genes) relative to other stages: four to eight and eight to sixteen cell stages, onset of circulation, pre- and post-hatch, and during complete yolk absorption. The fewest differences among adjacent stages occur during gastrulation. Yet, at stage 16 (pre-mid-gastrulation), the largest number of genes has peak expression. This stage has an over-representation of genes in oxidative respiration and protein expression (ribosomes, translational genes and proteases). Unexpectedly, among all ribosomal genes, both strong positive and negative correlations occur. Similar correlated patterns of expression occur among all significant genes. These data provide statistical support for the temporal dynamics of developmental gene expression during all stages of vertebrate development. A double-loop design was used for the microarray hybridizations, where each sample is hybridized to 2 arrays using both Cy3- and Cy5-labelled fluorophores (Kerr and Churchill 2001a; Kerr and Churchill 2001b). The loop consisted of Cy3- and Cy5-labelled embryo aRNAs from 4 biological pools for each of 40 stages (S). In total, 160 biological pools were hybridized to 80 microarrays. Each array had different combinations of biological pools (Altman and Hua 2006). The double loop formed was S1M-bM-^FM-^R S2 M-bM-^FM-^R S3M-bM-^FM-^R M-bM-^@M-& S40M-bM-^FM-^R S1 and S40M-bM-^FM-^R S39M-bM-^FM-^R S38M-bM-^FM-^R M-bM-^@M-& S2M-bM-^FM-^R S1 M-bM-^FM-^R S40, where each arrow represents a separate hybridization (array) with the biological pool at the base of the arrow labeled with Cy3 and the biological pool at the head of the arrow labelled with Cy5.

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The integrator complex subunit 6 (Ints6) confines the dorsal organizer in vertebrate embryogenesis.

Publications

The integrator complex subunit 6 (Ints6) confines the dorsal organizer in vertebrate embryogenesis.

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