scholarly journals foxc1a genetically interacts with ripply1 to regulate mesp-ba expression and somitogenesis in the zebrafish embryo

2016 ◽  
Author(s):  
Rotem Lavy ◽  
W. Ted Allison ◽  
Fred B. Berry
Keyword(s):  
Regulatory Network ◽  
Zebrafish Embryo ◽  
Temporal Order ◽  
Regulatory Mechanisms ◽  
Loss Of Function ◽  
Expression Domain ◽  
Somite Formation ◽  
Opposing Effects ◽  
Expression Loss ◽  
Time Point

AbstractSomitogenesis is a fundamental segmentation process that forms the vertebrate body plan. A network of transcription factors is essential in establishing the spatial temporal order of this process. One such transcription factor is mesp-ba which has an important role in determining somite boundary formation. Its expression in somitogenesis is tightly regulated by the transcriptional activator Tbx6 and the repressor Ripply1 via a feedback regulatory network. Loss of foxc1a function in zebrafish leads to lack of anterior somite formation and reduced mesp-ba expression. Here we examine how foxc1a interacts with the tbx6-ripply1 network to regulate mesp-ba expression. In foxc1a morphants, anterior somites did not form at 12.5 hours post fertilization (hpf). At 22 hpf posterior somites formed, whereas anterior somites remained absent. In ripply1 morphants, no somites were observed at any time point. The expression of mesp-ba was reduced in the foxc1a morphants and expanded anteriorly in ripply1 morphants. The tbx6 expression domain was smaller and shifted anteriorly in the foxc1a morphants. Double knockdown of foxc1a and ripply1 resulted in absence of anterior somite formation while posterior somites did form, suggesting a partial rescue of the ripply1 phenotype. However, unlike the single foxc1a morphants, expression of mesp-ba was restored in the anterior PSM. Expression of tbx6 was expanded anteriorly in the double morphants. In conclusion, both foxc1a and ripply1 morphants displayed defects in somitogenesis, but their individual loss of function had opposing effects on mesp-ba expression. Loss of ripply1 appears to have rescued the mesp-ba expression in the foxc1a morphant, suggesting that intersection of these parallel regulatory mechanisms is required for normal mesp-ba expression and somite formation.

Expression domains of a zebrafish homologue of the Drosophila pair-rule gene hairy correspond to primordia of alternating somites

Development ◽  
1996 ◽  
Vol 122 (7) ◽  
pp. 2071-2078 ◽  
Author(s):  
M. Muller ◽  
E. Weizsacker ◽  
J.A. Campos-Ortega
Keyword(s):  
Expression Pattern ◽  
Bhlh Protein ◽  
Presomitic Mesoderm ◽  
Tail Bud ◽  
Expression Domain ◽  
Somite Formation ◽  
Pair Rule Gene ◽  
Pair Rule ◽  
Time Point

her1 is a zebrafish cDNA encoding a bHLH protein with all features characteristic of members of the Drosophila HAIRY-E(SPL) family. During late gastrulation stages, her1 is expressed in the epibolic margin and in two distinct transverse bands of hypoblastic cells behind the epibolic front. After completion of epiboly, this pattern persists essentially unchanged through postgastrulation stages; the marginal domain is incorporated in the tail bud and, depending on the time point, either two or three paired bands of expressing cells are present within the paraxial presomitic mesoderm separated by regions devoid of transcripts. Labelling of cells within the her1 expression domains with fluorescein-dextran shows that the cells in the epibolic margin and the tail bud are not allocated to particular somites. However, allocation of cells to somites occurs between the marginal expression domain and the first expression band, anterior to it. Moreover, the her1 bands, and the intervening non-expressing zones, each represents the primordium of a somite. This expression pattern is highly reminiscent of that of Drosophila pair-rule genes. A possible participation of her1 in functions related to somite formation is discussed.

scholarly journals Screening Driving Transcription Factors in the Processing of Gastric Cancer

2016 ◽  
Vol 2016 ◽  
pp. 1-9 ◽  
Author(s):  
Guangzhong Xu ◽  
Kai Li ◽  
Nengwei Zhang ◽  
Bin Zhu ◽  
Guosheng Feng
Keyword(s):  
Gastric Cancer ◽  
Transcription Factors ◽  
Regulatory Network ◽  
Target Genes ◽  
Transcriptional Regulatory Network ◽  
Expression Profiles ◽  
Functional Enrichment ◽  
Regulatory Mechanisms ◽  
Integrated Analysis ◽  
Transcriptional Regulatory

Background. Construction of the transcriptional regulatory network can provide additional clues on the regulatory mechanisms and therapeutic applications in gastric cancer.Methods. Gene expression profiles of gastric cancer were downloaded from GEO database for integrated analysis. All of DEGs were analyzed by GO enrichment and KEGG pathway enrichment. Transcription factors were further identified and then a global transcriptional regulatory network was constructed.Results. By integrated analysis of the six eligible datasets (340 cases and 43 controls), a bunch of 2327 DEGs were identified, including 2100 upregulated and 227 downregulated DEGs. Functional enrichment analysis of DEGs showed that digestion was a significantly enriched GO term for biological process. Moreover, there were two important enriched KEGG pathways: cell cycle and homologous recombination. Furthermore, a total of 70 differentially expressed TFs were identified and the transcriptional regulatory network was constructed, which consisted of 566 TF-target interactions. The top ten TFs regulating most downstream target genes were BRCA1, ARID3A, EHF, SOX10, ZNF263, FOXL1, FEV, GATA3, FOXC1, and FOXD1. Most of them were involved in the carcinogenesis of gastric cancer.Conclusion. The transcriptional regulatory network can help researchers to further clarify the underlying regulatory mechanisms of gastric cancer tumorigenesis.

scholarly journals FIGNL1 associates with KIF1Bβ and BICD1 to restrict dynein transport velocity during axon navigation

2019 ◽  
Vol 218 (10) ◽  
pp. 3290-3306 ◽  
Author(s):  
Melody Atkins ◽  
Laïla Gasmi ◽  
Valérie Bercier ◽  
Céline Revenu ◽  
Filippo Del Bene ◽  
...  
Keyword(s):  
Molecular Motor ◽  
Motor Axon ◽  
Regulatory Mechanisms ◽  
Axon Pathfinding ◽  
Loss Of Function ◽  
Yeast Two Hybrid ◽  
Neuronal Connectivity ◽  
Transport Velocity ◽  
Bidirectional Transport ◽  
Two Hybrid

Neuronal connectivity relies on molecular motor-based axonal transport of diverse cargoes. Yet the precise players and regulatory mechanisms orchestrating such trafficking events remain largely unknown. We here report the ATPase Fignl1 as a novel regulator of bidirectional transport during axon navigation. Using a yeast two-hybrid screen and coimmunoprecipitation assays, we showed that Fignl1 binds the kinesin Kif1bβ and the dynein/dynactin adaptor Bicaudal D-1 (Bicd1) in a molecular complex including the dynactin subunit dynactin 1. Fignl1 colocalized with Kif1bβ and showed bidirectional mobility in zebrafish axons. Notably, Kif1bβ and Fignl1 loss of function similarly altered zebrafish motor axon pathfinding and increased dynein-based transport velocity of Rab3 vesicles in these navigating axons, pinpointing Fignl1/Kif1bβ as a dynein speed limiter complex. Accordingly, disrupting dynein/dynactin activity or Bicd1/Fignl1 interaction induced motor axon pathfinding defects characteristic of Fignl1 gain or loss of function, respectively. Finally, pharmacological inhibition of dynein activity partially rescued the axon pathfinding defects of Fignl1-depleted larvae. Together, our results identify Fignl1 as a key dynein regulator required for motor circuit wiring.

scholarly journals Arterial endoglin does not protect against arteriovenous malformations

Angiogenesis ◽  
2020 ◽  
Vol 23 (4) ◽  
pp. 559-566 ◽  
Author(s):  
Esha Singh ◽  
Rachael E. Redgrave ◽  
Helen M. Phillips ◽  
Helen M. Arthur
Keyword(s):  
Arteriovenous Malformations ◽  
Distal Part ◽  
Capillary Endothelium ◽  
Hereditary Haemorrhagic Telangiectasia ◽  
Vascular Disorder ◽  
Loss Of Function ◽  
Similar Frequency ◽  
Arterial Involvement ◽  
Time Point

Abstract Introduction Endoglin (ENG) forms a receptor complex with ALK1 in endothelial cells (ECs) to promote BMP9/10 signalling. Loss of function mutations in either ENG or ALK1 genes lead to the inherited vascular disorder hereditary haemorrhagic telangiectasia (HHT), characterised by arteriovenous malformations (AVMs). However, the vessel-specific role of ENG and ALK1 proteins in protecting against AVMs is unclear. For example, AVMs have been described to initiate in arterioles, whereas ENG is predominantly expressed in venous ECs. To investigate whether ENG has any arterial involvement in protecting against AVM formation, we specifically depleted the Eng gene in venous and capillary endothelium whilst maintaining arterial expression, and investigated how this affected the incidence and location of AVMs in comparison with pan-endothelial Eng knockdown. Methods Using the mouse neonatal retinal model of angiogenesis, we first established the earliest time point at which Apj-Cre-ERT2 activity was present in venous and capillary ECs but absent from arterial ECs. We then compared the incidence of AVMs following pan-endothelial or venous/capillary-specific ENG knockout. Results Activation of Apj-Cre-ERT2 with tamoxifen from postnatal day (P) 5 ensured preservation of arterial ENG protein expression. Specific loss of ENG expression in ECs of veins and capillaries led to retinal AVMs at a similar frequency to pan-endothelial loss of ENG. AVMs occurred in the proximal as well as the distal part of the retina consistent with a defect in vascular remodelling during maturation of the vasculature. Conclusion Expression of ENG is not required in arterial ECs to protect against AVM formation.

scholarly journals Dynamic regulatory module networks for inference of cell type specific transcriptional networks

2020 ◽  
Author(s):  
Alireza Fotuhi Siahpirani ◽  
Deborah Chasman ◽  
Morten Seirup ◽  
Sara Knaack ◽  
Rupa Sridharan ◽  
...  
Keyword(s):  
Regulatory Network ◽  
Regulatory Networks ◽  
Network Dynamics ◽  
Cell Types ◽  
Small Sample ◽  
Cell Type ◽  
Regulatory Module ◽  
A Cell ◽  
Cell Type Specific ◽  
Time Point

AbstractChanges in transcriptional regulatory networks can significantly alter cell fate. To gain insight into transcriptional dynamics, several studies have profiled transcriptomes and epigenomes at different stages of a developmental process. However, integrating these data across multiple cell types to infer cell type specific regulatory networks is a major challenge because of the small sample size for each time point. We present a novel approach, Dynamic Regulatory Module Networks (DRMNs), to model regulatory network dynamics on a cell lineage. DRMNs represent a cell type specific network by a set of expression modules and associated regulatory programs, and probabilistically model the transitions between cell types. DRMNs learn a cell type’s regulatory network from input expression and epigenomic profiles using multi-task learning to exploit cell type relatedness. We applied DRMNs to study regulatory network dynamics in two different developmental dynamic processes including cellular reprogramming and liver dedifferentiation. For both systems, DRMN predicted relevant regulators driving the major patterns of expression in each time point as well as regulators for transitioning gene sets that change their expression over time.

scholarly journals Spatial specification of mammalian eye territories by reciprocal transcriptional repression of Pax2 and Pax6

Development ◽  
2000 ◽  
Vol 127 (20) ◽  
pp. 4325-4334 ◽  
Author(s):  
M. Schwarz ◽  
F. Cecconi ◽  
G. Bernier ◽  
N. Andrejewski ◽  
B. Kammandel ◽  
...  
Keyword(s):  
Visual System ◽  
Transcriptional Repression ◽  
Ectopic Expression ◽  
Pax6 Gene ◽  
Loss Of Function ◽  
Pax6 Expression ◽  
Expression Domain ◽  
Enhancer Activity ◽  
Optic Stalk ◽  
Optic Cup

We have studied the molecular basis of the Pax2 and Pax6 function in the establishment of visual system territories. Loss-of-function mutants have revealed crucial roles for Pax2 in the generation of the optic stalk and for Pax6 in the development of the optic cup. Ectopic expression of Pax6 in the optic stalk under control of Pax2 promoter elements resulted in a shift of the optic cup/optic stalk boundary indicated by the presence of retinal pigmented cells on the optic stalk. By studying mouse embryos at early developmental stages we detected an expansion of Pax2 expression domain in the Pax6(−/−) mutant and of Pax6 expression domain in the Pax2(−/−) embryo. These results suggest that the position of the optic cup/optic stalk boundary depends on Pax2 and Pax6 expression, hinting at a possible molecular interaction. Using gel shift experiments, we confirmed the presence of Pax2- and Pax6-binding sites on the retina enhancer of the Pax6 gene and on the Pax2 upstream control region, respectively. Co-transfection experiments revealed a reciprocal inhibition of Pax2 promoter/enhancer activity by Pax6 protein and vice versa. Based on our findings, we propose a model for Pax gene regulation that establishes the proper spatial regionalization of the mammalian visual system.

scholarly journals Reverse Engineering of the Pediatric Sepsis Regulatory Network and Identification of Master Regulators

Biomedicines ◽  
2021 ◽  
Vol 9 (10) ◽  
pp. 1297
Author(s):  
Raffael Azevedo de Carvalho Oliveira ◽  
Danilo Oliveira Imparato ◽  
Vítor Gabriel Saldanha Fernandes ◽  
João Vitor Ferreira Cavalcante ◽  
Ricardo D’Oliveira Albanus ◽  
...  
Keyword(s):  
Gene Expression ◽  
Retrospective Study ◽  
Regulatory Network ◽  
Regulatory Mechanisms ◽  
Master Regulators ◽  
Genetic Biomarkers ◽  
Promising Strategy ◽  
The World ◽  
Pediatric Sepsis ◽  
Increased Activity

Sepsis remains a leading cause of death in ICUs all over the world, with pediatric sepsis accounting for a high percentage of mortality in pediatric ICUs. Its complexity makes it difficult to establish a consensus on genetic biomarkers and therapeutic targets. A promising strategy is to investigate the regulatory mechanisms involved in sepsis progression, but there are few studies regarding gene regulation in sepsis. This work aimed to reconstruct the sepsis regulatory network and identify transcription factors (TFs) driving transcriptional states, which we refer to here as master regulators. We used public gene expression datasets to infer the co-expression network associated with sepsis in a retrospective study. We identified a set of 15 TFs as potential master regulators of pediatric sepsis, which were divided into two main clusters. The first cluster corresponded to TFs with decreased activity in pediatric sepsis, and GATA3 and RORA, as well as other TFs previously implicated in the context of inflammatory response. The second cluster corresponded to TFs with increased activity in pediatric sepsis and was composed of TRIM25, RFX2, and MEF2A, genes not previously described as acting in a coordinated way in pediatric sepsis. Altogether, these results show how a subset of master regulators TF can drive pathological transcriptional states, with implications for sepsis biology and treatment.

scholarly journals Early asymmetric cues triggering the dorsal/ventral gene regulatory network of the sea urchin embryo

eLife ◽  
2014 ◽  
Vol 3 ◽  
Author(s):  
Vincenzo Cavalieri ◽  
Giovanni Spinelli
Keyword(s):  
Gene Regulatory Network ◽  
Sea Urchin ◽  
Regulatory Network ◽  
Ectopic Expression ◽  
Paracentrotus Lividus ◽  
Loss Of Function ◽  
Mapk Activity ◽  
Sea Urchin Embryo ◽  
Gene Regulatory ◽  
Dorsal Cells

Dorsal/ventral (DV) patterning of the sea urchin embryo relies on a ventrally-localized organizer expressing Nodal, a pivotal regulator of the DV gene regulatory network. However, the inceptive mechanisms imposing the symmetry-breaking are incompletely understood. In Paracentrotus lividus, the Hbox12 homeodomain-containing repressor is expressed by prospective dorsal cells, spatially facing and preceding the onset of nodal transcription. We report that Hbox12 misexpression provokes DV abnormalities, attenuating nodal and nodal-dependent transcription. Reciprocally, impairing hbox12 function disrupts DV polarity by allowing ectopic expression of nodal. Clonal loss-of-function, inflicted by blastomere transplantation or gene-transfer assays, highlights that DV polarization requires Hbox12 action in dorsal cells. Remarkably, the localized knock-down of nodal restores DV polarity of embryos lacking hbox12 function. Finally, we show that hbox12 is a dorsal-specific negative modulator of the p38-MAPK activity, which is required for nodal expression. Altogether, our results suggest that Hbox12 function is essential for proper positioning of the DV organizer.

scholarly journals Simulating Microinjection Experiments in a Novel Model of the Rat Sleep-Wake Regulatory Network

2010 ◽  
Vol 103 (4) ◽  
pp. 1937-1953 ◽  
Author(s):  
Cecilia G. Diniz Behn ◽  
Victoria Booth
Keyword(s):  
Mathematical Modeling ◽  
Brain Stem ◽  
Rem Sleep ◽  
Regulatory Network ◽  
State Dependence ◽  
Nrem Sleep ◽  
External Noise ◽  
Modeling Framework ◽  
Neuronal Nuclei ◽  
Opposing Effects

This study presents a novel mathematical modeling framework that is uniquely suited to investigating the structure and dynamics of the sleep-wake regulatory network in the brain stem and hypothalamus. It is based on a population firing rate model formalism that is modified to explicitly include concentration levels of neurotransmitters released to postsynaptic populations. Using this framework, interactions among primary brain stem and hypothalamic neuronal nuclei involved in rat sleep-wake regulation are modeled. The model network captures realistic rat polyphasic sleep-wake behavior consisting of wake, rapid eye movement (REM) sleep, and non-REM (NREM) sleep states. Network dynamics include a cyclic pattern of NREM sleep, REM sleep, and wake states that is disrupted by simulated variability of neurotransmitter release and external noise to the network. Explicit modeling of neurotransmitter concentrations allows for simulations of microinjections of neurotransmitter agonists and antagonists into a key wake-promoting population, the locus coeruleus (LC). Effects of these simulated microinjections on sleep-wake states are tracked and compared with experimental observations. Agonist/antagonist pairs, which are presumed to have opposing effects on LC activity, do not generally induce opposing effects on sleep-wake patterning because of multiple mechanisms for LC activation in the network. Also, different agents, which are presumed to have parallel effects on LC activity, do not induce parallel effects on sleep-wake patterning because of differences in the state dependence or independence of agonist and antagonist action. These simulation results highlight the utility of formal mathematical modeling for constraining conceptual models of the sleep-wake regulatory network.

scholarly journals Geminin Orchestrates Somite Formation by Regulating Fgf8 and Notch Signaling

2018 ◽  
Vol 2018 ◽  
pp. 1-13
Author(s):  
Wei Huang ◽  
Yu Zhang ◽  
Kang Cao ◽  
Lingfei Luo ◽  
Sizhou Huang
Keyword(s):  
Notch Signaling ◽  
Signaling Pathways ◽  
Critical Factor ◽  
Loss Of Function ◽  
Presomitic Mesoderm ◽  
Tail Bud ◽  
Notch Activity ◽  
Somite Formation ◽  
First Time

During somitogenesis, Fgf8 maintains the predifferentiation stage of presomitic mesoderm (PSM) cells and its retraction gives a cue for somite formation. Delta/Notch initiates the expression of oscillation genes in the tail bud and subsequently contributes to somite formation in a periodic way. Whether there exists a critical factor coordinating Fgf8 and Notch signaling pathways is largely unknown. Here, we demonstrate that the loss of function of geminin gave rise to narrower somites as a result of derepressed Fgf8 gradient in the PSM and tail bud. Furthermore, in geminin morphants, the somite boundary could not form properly but the oscillation of cyclic genes was normal, displaying the blurry somitic boundary and disturbed somite polarity along the AP axis. In mechanism, these manifestations were mediated by the disrupted association of the geminin/Brg1 complex with intron 3 of mib1. The latter interaction was found to positively regulate mib1 transcription, Notch activity, and sequential somite segmentation during somitogenesis. In addition, geminin was also shown to regulate the expression of deltaD in mib1-independent way. Collectively, our data for the first time demonstrate that geminin regulates Fgf8 and Notch signaling to regulate somite segmentation during somitogenesis.

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