Conservation of Pax-6 in a lower chordate, the ascidian Phallusia mammillata

Development ◽  
1997 ◽  
Vol 124 (4) ◽  
pp. 817-825 ◽  
Author(s):  
S. Glardon ◽  
P. Callaerts ◽  
G. Halder ◽  
W.J. Gehring
Keyword(s):  
Ectopic Expression ◽  
Regulatory Function ◽  
Homologous Gene ◽  
Loss Of Function ◽  
Tailbud Stage ◽  
The Central Nervous System ◽  
Targeted Expression ◽  
Lower Chordate ◽  
Important Position ◽  
Conserved Gene

The Pax-6 genes of vertebrates and invertebrates encode transcription factors with both a paired domain and a homeodomain. They are expressed in the developing eye and in the central nervous system. Loss-of-function mutations in mammals and in flies result in a reduction or absence of eyes and targeted expression of the Drosophila and the mouse Pax-6 genes induces ectopic eye structures in Drosophila. These findings lead to the proposal that the morphogenesis of the different types of eyes is controlled by a Pax-6-dependent genetic pathway and that the various eye types are of monophyletic origin. We have isolated a Pax-6 homologous gene from the ascidian Phallusia mammillata, because ascidians occupy an important position in early chordate evolution. Furthermore, the Phallusia larva has a simple photosensitive ocellus. Phallusia Pax-6 shares extensive sequence identity and conserved genomic organization with the known Pax-6 genes of vertebrates and invertebrates. Expression of Phallusia Pax-6 is first detected at late gastrula stages in distinct regions of the developing neural plate. At the tailbud stage, it is expressed in the spinal cord and the brain vesicle, where the sensory organs (ocellus and otolith) form, suggesting an important function in their development. Ectopic expression of the ascidian Pax-6 gene in Drosophila leads to the induction of supernumerary eyes indicating a highly conserved gene regulatory function for Pax-6 genes.

scholarly journals A novel Dbl family RhoGEF promotes Rho-dependent axon attraction to the central nervous system midline in Drosophila and overcomes Robo repulsion

2001 ◽  
Vol 155 (7) ◽  
pp. 1117-1122 ◽  
Author(s):  
Greg J. Bashaw ◽  
Hailan Hu ◽  
Catherine D. Nobes ◽  
Corey S. Goodman
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Rho Gtpases ◽  
Ectopic Expression ◽  
Nucleotide Exchange ◽  
Loss Of Function ◽  
Guanine Nucleotide Exchange ◽  
Positive Regulators ◽  
The Central Nervous System ◽  
Rho Gef

The key role of the Rho family GTPases Rac, Rho, and CDC42 in regulating the actin cytoskeleton is well established (Hall, A. 1998. Science. 279:509–514). Increasing evidence suggests that the Rho GTPases and their upstream positive regulators, guanine nucleotide exchange factors (GEFs), also play important roles in the control of growth cone guidance in the developing nervous system (Luo, L. 2000. Nat. Rev. Neurosci. 1:173–180; Dickson, B.J. 2001. Curr. Opin. Neurobiol. 11:103–110). Here, we present the identification and molecular characterization of a novel Dbl family Rho GEF, GEF64C, that promotes axon attraction to the central nervous system midline in the embryonic Drosophila nervous system. In sensitized genetic backgrounds, loss of GEF64C function causes a phenotype where too few axons cross the midline. In contrast, ectopic expression of GEF64C throughout the nervous system results in a phenotype in which far too many axons cross the midline, a phenotype reminiscent of loss of function mutations in the Roundabout (Robo) repulsive guidance receptor. Genetic analysis indicates that GEF64C expression can in fact overcome Robo repulsion. Surprisingly, evidence from genetic, biochemical, and cell culture experiments suggests that the promotion of axon attraction by GEF64C is dependent on the activation of Rho, but not Rac or Cdc42.

scholarly journals miR-637 prevents glioblastoma progression by interrupting ZEB2/WNT/β-catenin cascades

2021 ◽  
Author(s):  
Wei Wang ◽  
Zilong Zhou ◽  
Shuai Han ◽  
Di Wu
Keyword(s):  
Phase Transition ◽  
Central Nervous System ◽  
Cell Proliferation ◽  
Ectopic Expression ◽  
S Phase ◽  
Signaling Cascades ◽  
Loss Of Function ◽  
The Central Nervous System ◽  
Canonical Wnt ◽  
Tumor Growth Suppression

Abstract Glioblastomas (GBMs) are the most frequent primary malignancies in the central nervous system. Aberrant activation of WNT/β-catenin signaling pathways is critical for GBM malignancy. However, the regulation of WNT/β-catenin signaling cascades remains unclear. Presently, we observed the increased expression of ZEB2 and decreased expression of miR-637 in GBM. The expression of miR-637 was negatively correlated with expression of ZEB2. miR-637 overexpression overcame the ZEB2-enhanced cell proliferation and G1/S phase transition. In addition, miR-637 suppressed canonical WNT/β-catenin pathways by targeting WNT7A directly. Gain- and loss-of-function experiments in U251 mice demonstrated that miR-637 inhibited cell proliferation and arrested the G1/S phase transition, leading to tumor growth suppression. The collective findings suggest that ZEB2 and WNT/β-catenin cascades merge at miR-637 and the ectopic expression of miR-637 disturbs ZEB2/WNT/β-Catenin-mediated GBM growth. The findings should inform improved β-catenin-targeted therapy against GBM.

scholarly journals Rab11 negatively regulates Wingless preventing JNK mediated apoptosis inDrosophilaepithelium during embryonic dorsal closure

2021 ◽  
Author(s):  
Nabarun Nandy ◽  
Jagat Kumar Roy
Keyword(s):  
Wound Healing ◽  
Epithelial Cells ◽  
Signaling Pathways ◽  
Healing Process ◽  
Ectopic Expression ◽  
Wound Healing Process ◽  
Dorsal Closure ◽  
Loss Of Function ◽  
Upstream Regulator ◽  
Conserved Gene

AbstractCell signaling pathways involved in epithelial wound healing, show a lot of complexities when it comes to their regulation. Remarkably, a large proportion of these signaling pathways are triggered at the time of morphogenetic events which usually involve epithelial sheet fusions during embryonic development, such as the event of dorsal cloure in Drosophila embryos. One such conserved pathway in the wound healing process is the JNK-Dpp signaling pathway. Recent observations suggest that one such upstream regulator of JNK mediated apoptosis could be Rab11, a small Ras like GTPase, which is functionally associated with the membrane and cortical cytoskeletal organization of epithelial cells. UsingDrosophilaembryonic dorsal closure as a model of wound healing, we observed that a targeted expression of aRab11loss of function mutant in the dorso-lateral epidermis of fly embryos (tissue which extends contra-laterally in order to fill the intervening gap) undergoing dorsal closure leads to an ectopic expression of Caspase-3 and a concomitant up-regulation of the JNK-Dpp signaling. This resulted in the death of the dorso-lateral epithelial cells with a consequent embryonic lethality due to dorsal closure defects. Interestingly, a simultaneous knockdown ofwingless(another developmentally conserved gene) inRab11mutants resulted in a rescue of the lethal phenotype and also a significant level of successful completion of the dorsal closure process. In our experiments we suggest Rab11 could promote cross talk between the JNK-Dpp pathway and the canonicalwinglesspathway in the regulation of apoptosis in the dorsolateral epithelium of fly embryos undergoing dorsal closure.One Sentence SummaryRab11 functions through a conserved Wingless mediated JNK-Dpp pathway during embryonic dorsal closure.

The Regulatory Function of the Molecular Chaperone Hsp90 in the Cell Wall Integrity of Pathogenic Fungi

2018 ◽  
Vol 16 (1) ◽  
pp. 44-53
Author(s):  
Marina Campos Rocha ◽  
Camilla Alves Santos ◽  
Iran Malavazi
Keyword(s):  
Cell Wall ◽  
Antifungal Therapy ◽  
Molecular Chaperone ◽  
Regulatory Protein ◽  
Pathogenic Fungi ◽  
Antifungal Drugs ◽  
Cell Wall Integrity ◽  
Regulatory Function ◽  
Loss Of Function ◽  
Hsp90 Inhibition

Different signaling cascades including the Cell Wall Integrity (CWI), the High Osmolarity Glycerol (HOG) and the Ca2+/calcineurin pathways control the cell wall biosynthesis and remodeling in fungi. Pathogenic fungi, such as Aspergillus fumigatus and Candida albicans, greatly rely on these signaling circuits to cope with different sources of stress, including the cell wall stress evoked by antifungal drugs and the host’s response during infection. Hsp90 has been proposed as an important regulatory protein and an attractive target for antifungal therapy since it stabilizes major effector proteins that act in the CWI, HOG and Ca2+/calcineurin pathways. Data from the human pathogen C. albicans have provided solid evidence that loss-of-function of Hsp90 impairs the evolution of resistance to azoles and echinocandin drugs. In A. fumigatus, Hsp90 is also required for cell wall integrity maintenance, reinforcing a coordinated function of the CWI pathway and this essential molecular chaperone. In this review, we focus on the current information about how Hsp90 impacts the aforementioned signaling pathways and consequently the homeostasis and maintenance of the cell wall, highlighting this cellular event as a key mechanism underlying antifungal therapy based on Hsp90 inhibition.

scholarly journals ATP13A2 Regulates Cellular α-Synuclein Multimerization, Membrane Association, and Externalization

2021 ◽  
Vol 22 (5) ◽  
pp. 2689
Author(s):  
Jianmin Si ◽  
Chris Van den Haute ◽  
Evy Lobbestael ◽  
Shaun Martin ◽  
Sarah van Veen ◽  
...  
Keyword(s):  
Membrane Integrity ◽  
Ubiquitin Proteasome System ◽  
Regulatory Function ◽  
Membrane Association ◽  
Loss Of Function ◽  
Atypical Form ◽  
Polyamine Transport ◽  
Independent Functions ◽  
Ubiquitin Proteasome ◽  
The Impact

ATP13A2, a late endo-/lysosomal polyamine transporter, is implicated in a variety of neurodegenerative diseases, including Parkinson’s disease and Kufor–Rakeb syndrome, an early-onset atypical form of parkinsonism. Loss-of-function mutations in ATP13A2 result in lysosomal deficiency as a consequence of impaired lysosomal export of the polyamines spermine/spermidine. Furthermore, accumulating evidence suggests the involvement of ATP13A2 in regulating the fate of α-synuclein, such as cytoplasmic accumulation and external release. However, no consensus has yet been reached on the mechanisms underlying these effects. Here, we aimed to gain more insight into how ATP13A2 is linked to α-synuclein biology in cell models with modified ATP13A2 activity. We found that loss of ATP13A2 impairs lysosomal membrane integrity and induces α-synuclein multimerization at the membrane, which is enhanced in conditions of oxidative stress or exposure to spermine. In contrast, overexpression of ATP13A2 wildtype (WT) had a protective effect on α-synuclein multimerization, which corresponded with reduced αsyn membrane association and stimulation of the ubiquitin-proteasome system. We also found that ATP13A2 promoted the secretion of α-synuclein through nanovesicles. Interestingly, the catalytically inactive ATP13A2 D508N mutant also affected polyubiquitination and externalization of α-synuclein multimers, suggesting a regulatory function independent of the ATPase and transport activity. In conclusion, our study demonstrates the impact of ATP13A2 on α-synuclein multimerization via polyamine transport dependent and independent functions.

scholarly journals Long noncoding RNA FER1L4 promotes the malignant processes of papillary thyroid cancer by targeting the miR-612/ Cadherin 4 axis

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Luyao Wu ◽  
Yu Ding ◽  
Houchao Tong ◽  
Xi Zhuang ◽  
Jingsheng Cai ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Papillary Thyroid Cancer ◽  
Noncoding Rna ◽  
Animal Experiments ◽  
Ectopic Expression ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Papillary Thyroid ◽  
Loss Of Function ◽  
Functional Roles

Abstract Background Long noncoding RNAs (lncRNAs) have emerged as crucial regulators in various cancers. However, the functional roles of most lncRNA in papillary thyroid cancer (PTC) are not detailly understood. This study aims to investigate the biological function and molecular mechanism of lncRNA Fer-1 like family member 4 (FER1L4) in PTC. Methods The expression of FER1L4 in PTC was determined via operating quantitative real-time PCR assays. Meanwhile, the clinical significance of FER1L4 in patients with PTC was described. The biological functions of FER1L4 on PTC cells were evaluated by gain and loss of function experiments. Moreover, animal experiments were performed to reveal the effect on tumor growth. Subcellular distribution of FER1L4 was determined by fluorescence in situ hybridization and subcellular localization assays. Luciferase reporter assay and RNA immunoprecipitation assay were applied to define the relationship between FER1L4, miR-612, and Cadherin 4 (CDH4). Results Upregulated expression of FER1L4 in PTC tissues was positively correlated with lymph node metastasis (P = 0.020), extrathyroidal extension (P = 0.013) and advanced TNM stages (P = 0.013). In addition, knockdown of FER1L4 suppressed PTC cell proliferation, migration, and invasion, whereas ectopic expression of FER1L4 inversely promoted these processes. Mechanistically, FER1L4 could competitively bind with miR-612 to prevent the degradation of its target gene CDH4. This condition was further confirmed in the rescue assays. Conclusions This study first demonstrates FER1L4 plays an oncogenic role in PTC via a FER1L4-miR-612-CDH4 axis and may provide new therapeutic and diagnostic targets for PTC.

scholarly journals Partitioning of N-Ethylmaleimide-Sensitive Fusion (NSF) Protein Function in Drosophila melanogaster: dNSF1 Is Required in the Nervous System, and dNSF2 Is Required in Mesoderm

Genetics ◽  
2001 ◽  
Vol 158 (1) ◽  
pp. 265-278
Author(s):  
Jessica A Golby ◽  
Leigh Anna Tolar ◽  
Leo Pallanck
Keyword(s):  
Nervous System ◽  
Protein Function ◽  
Ectopic Expression ◽  
Drosophila Genome ◽  
Loss Of Function ◽  
Stage Of Development ◽  
Expression Studies ◽  
Larval Nervous System ◽  
Constitutive Secretion ◽  
Temporal And Spatial

Abstract The N-ethylmaleimide-sensitive fusion protein (NSF) promotes the fusion of secretory vesicles with target membranes in both regulated and constitutive secretion. While it is thought that a single NSF may perform this function in many eukaryotes, previous work has shown that the Drosophila genome contains two distinct NSF genes, dNSF1 and dNSF2, raising the possibility that each plays a specific secretory role. To explore this possibility, we generated mutations in the dNSF2 gene and used these and novel dNSF1 loss-of-function mutations to analyze the temporal and spatial requirements and the degree of functional redundancy between dNSF1 and dNSF2. Results of this analysis indicate that dNSF1 function is required in the nervous system beginning at the adult stage of development and that dNSF2 function is required in mesoderm beginning at the first instar larval stage of development. Additional evidence suggests that dNSF1 and dNSF2 may play redundant roles during embryonic development and in the larval nervous system. Ectopic expression studies demonstrate that the dNSF1 and dNSF2 gene products can functionally substitute for one another. These results indicate that the Drosophila NSF proteins exhibit similar functional properties, but have evolved distinct tissue-specific roles.

scholarly journals Crosstalk of CREB and Fos/Jun on a single cis-element: transcriptional repression of the steroidogenic acute regulatory protein gene

2007 ◽  
Vol 39 (4) ◽  
pp. 261-277 ◽  
Author(s):  
Pulak R Manna ◽  
Douglas M Stocco
Keyword(s):  
Transcriptional Repression ◽  
Protein Gene ◽  
Binding Protein ◽  
Regulatory Protein ◽  
Ectopic Expression ◽  
Fine Tuning ◽  
Creb Binding Protein ◽  
Loss Of Function ◽  
Cis Element ◽  
Steroidogenic Acute Regulatory

AbstractTranscriptional regulation of the steroidogenic acute regulatory (StAR) protein gene by cAMP-dependent mechanisms occurs in the absence of a consensus cAMP-response element (CRE; TGACGTCA) and is mediated by several sequence-specific transcription factors. We previously identified three CRE-like sites (within the −151/−1 bp cAMP-responsive region of the mouse StAR gene), of which the CRE2 site overlaps with an activator protein-1 (AP-1) motif (TGACTGA, designated as CRE2/AP-1) that can bind both CRE and AP-1 DNA-binding proteins. The present studies were aimed at exploring the functional crosstalk between CREB (CRE-binding protein) and cFos/cJun (AP-1 family members) on the CRE2/AP-1 element and its role in regulating transcription of the StAR gene. Using MA-10 mouse Leydig tumor cells, we demonstrate that the CRE and AP-1 families of proteins interact with the CRE2/AP-1 sequence. CREB, cFos, and cJun proteins were found to bind to the CRE2/AP-1 motif but not the CRE1 and CRE3 sites. Treatment with the cAMP analog (Bu)2cAMP augmented phosphorylation of CREB (Ser133), cFos (Thr325), and cJun (ser73). Chromatin immunoprecipitation studies revealed that the induction of CREB, cFos, and cJun by (Bu)2cAMP was correlated with protein–DNA interactions and recruitment of the coactivator CREB-binding protein (CBP) to the StAR promoter. EMSA studies employing CREB and cFos/cJun proteins demonstrated competition between these factors for binding to the CRE2/AP-1 motif. Transfection of cells containing the −151/−1 StAR reporter with CREB and cFos/cJun resulted in trans-repression of the StAR gene, an event tightly associated with CBP, demonstrating that both CREB and Fos/Jun compete with each other for binding with limited amounts of intracellular CBP. Overexpression of adenovirus E1A, which binds and inactivates CBP, markedly suppressed StAR gene expression. Ectopic expression of CBP eliminated the repression of the StAR gene by E1A and potentiated the activity of CREB and cFos/cJun on StAR promoter responsiveness. These findings identify molecular events involved in crosstalk between CREB and cFos/cJun, which confer both gain and loss of function on a single cis-element in fine-tuning of the regulatory events involved in transcription of the StAR gene.

scholarly journals The Ubiquitously Expressed Csk Adaptor Protein Cbp Is Dispensable for Embryogenesis and T-Cell Development and Function

2005 ◽  
Vol 25 (23) ◽  
pp. 10533-10542 ◽  
Author(s):  
Marc-Werner Dobenecker ◽  
Christian Schmedt ◽  
Masato Okada ◽  
Alexander Tarakhovsky
Keyword(s):  
T Cell ◽  
Adaptor Protein ◽  
Regulatory Function ◽  
Loss Of Function ◽  
Thymic Development ◽  
Cell Functions ◽  
Carboxy Terminal ◽  
And Function

ABSTRACT Regulation of Src family kinase (SFK) activity is indispensable for a functional immune system and embryogenesis. The activity of SFKs is inhibited by the presence of the carboxy-terminal Src kinase (Csk) at the cell membrane. Thus, recruitment of cytosolic Csk to the membrane-associated SFKs is crucial for its regulatory function. Previous studies utilizing in vitro and transgenic models suggested that the Csk-binding protein (Cbp), also known as phosphoprotein associated with glycosphingolipid microdomains (PAG), is the membrane adaptor for Csk. However, loss-of-function genetic evidence to support this notion was lacking. Herein, we demonstrate that the targeted disruption of the cbp gene in mice has no effect on embryogenesis, thymic development, or T-cell functions in vivo. Moreover, recruitment of Csk to the specialized membrane compartment of “lipid rafts” is not impaired by Cbp deficiency. Our results indicate that Cbp is dispensable for the recruitment of Csk to the membrane and that another Csk adaptor, yet to be discovered, compensates for the loss of Cbp.

scholarly journals Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) in Physiological and Pathological Processes within the Gastrointestinal Tract: A Review

2021 ◽  
Vol 22 (16) ◽  
pp. 8682
Author(s):  
Aleksandra Karpiesiuk ◽  
Katarzyna Palus
Keyword(s):  
Adenylate Cyclase ◽  
Smooth Muscle Contraction ◽  
Regulatory Function ◽  
Gi Tract ◽  
Cytoprotective Effect ◽  
Neoplastic Processes ◽  
Pituitary Adenylate Cyclase ◽  
Pleiotropic Action ◽  
Tract Function ◽  
The Central Nervous System

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide widely distributed in the central nervous system (CNS) and many peripheral organs, such as the digestive tract, endocrine, reproductive and respiratory systems, where it plays different regulatory functions and exerts a cytoprotective effect. The multifarious physiological effects of PACAP are mediated through binding to different G protein-coupled receptors, including PAC1 (PAC1-R), VPAC1 (VPAC1-R) and VPAC2 (VPAC2-R) receptors. In the gastrointestinal (GI) tract, PACAP plays an important regulatory function. PACAP stimulates the secretion of digestive juices and hormone release, regulates smooth muscle contraction, local blood flow, cell migration and proliferation. Additionally, there are many reports confirming the involvement of PACAP in pathological processes within the GI tract, including inflammatory states, neuronal injury, diabetes, intoxication and neoplastic processes. The purpose of this review is to summarize the distribution and pleiotropic action of PACAP in the control of GI tract function and its cytoprotective effect in the course of GI tract disorders.

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