scholarly journals SPOP and CUL3 Modulate the Sonic Hedgehog Signal Response Through Controlled Degradation of GLI Family Transcription Factors

2021 ◽  
Vol 9 ◽  
Author(s):  
Patricia A. Umberger ◽  
Stacey K. Ogden
Keyword(s):  
Transcription Factors ◽  
Molecular Mechanisms ◽  
Evolutionary Divergence ◽  
Transcriptional Responses ◽  
Cubitus Interruptus ◽  
Functional Conservation ◽  
Gli Transcription Factors ◽  
Health And Disease ◽  
Key Driver ◽  
Broad Complex

The speckle-type POZ protein (SPOP) functions as a guardian of genome integrity and controls transcriptional regulation by functioning as a substrate adaptor for CUL3/RING-type E3 ubiquitin ligase complexes. SPOP-containing CUL3 complexes target a myriad of DNA-binding proteins involved in DNA repair and gene expression, and as such, are essential modulators of cellular homeostasis. GLI transcription factors are effectors of the Hedgehog (HH) pathway, a key driver of tissue morphogenesis and post-developmental homeostasis that is commonly corrupted in cancer. CUL3-SPOP activity regulates amplitude and duration of HH transcriptional responses by controlling stability of GLI family members. SPOP and GLI co-enrich in phase separated nuclear droplets that are thought to serve as hot spots for CUL3-mediated GLI ubiquitination and degradation. A similar framework exists in Drosophila, in which the Hedgehog-induced MATH (meprin and traf homology) and BTB (bric à brac, tramtrack, broad complex) domain containing protein (HIB) targets the GLI ortholog Cubitus interruptus (Ci) for Cul3-directed proteolysis. Despite this functional conservation, the molecular mechanisms by which HIB and SPOP contribute to Drosophila and vertebrate HH signaling differ. In this mini-review we highlight similarities between the two systems and discuss evolutionary divergence in GLI/Ci targeting that informs our understanding of how the GLI transcriptional code is controlled by SPOP and CUL3 in health and disease.

scholarly journals An ancient role for Collier/Olf/Ebf (COE)-type transcription factors in axial motor neuron development

2018 ◽  
Author(s):  
Catarina Catela ◽  
Edgar Correa ◽  
Jihad Aburas ◽  
Laura Croci ◽  
G. Giacomo Consalez ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Motor Neuron ◽  
Molecular Mechanisms ◽  
Neuron Development ◽  
Spinal Alignment ◽  
Knock Out ◽  
Transgenic Expression ◽  
C Elegans ◽  
Functional Conservation ◽  
Motor Circuits

ABSTRACTBackgroundMammalian motor circuits display remarkable cellular diversity with hundreds of motor neuron (MN) subtypes innervating hundreds of different muscles. Extensive research on limb muscle-innervating MNs has begun to elucidate the genetic programs that control animal locomotion. In striking contrast, the molecular mechanisms underlying the development of axial muscle-innervating MNs, which control breathing and spinal alignment, are poorly studied.MethodsOur previous studies indicated that the function of the Collier/Olf/Ebf (COE) family of transcription factors (TFs) in axial MN development may be conserved from nematodes to simple chordates. Here, we examine the expression pattern of all four mouse COE family members (mEbf1-mEbf4) in spinal MNs and employ genetic approaches in both nematodes and mice to investigate their function in axial MN development.ResultsWe report that mEbf1 and mEbf2 are expressed in distinct MN clusters (termed “columns”) that innervate different axial muscles. Mouse Ebf1 is expressed in MNs of the hypaxial motor column (HMC), which is necessary for breathing, while mEbf2 is expressed in MNs of the medial motor column (MMC) that control spinal alignment. Our characterization of Ebf2 knock-out mice revealed a requirement for Ebf2 in the differentiation of a subset of MMC MNs, indicating molecular diversity within MMC neurons. Intriguingly, transgenic expression of mEbf1 or mEbf2 can rescue axial MN differentiation and locomotory defects in nematodes (Caenorhabditis elegans) lacking unc-3, the sole C. elegans ortholog of the COE family, suggesting functional conservation among mEbf1, mEbf2 and nematode UNC-3.ConclusionsThese findings support the hypothesis that the genetic programs controlling axial MN development are deeply conserved across species, and further advance our understanding of such programs by revealing an essential role for Ebf2 in mouse axial MNs. Because human mutations in COE ortholgs lead to neurodevelopmental disorders characterized by motor developmental delay, our findings may advance our understanding of these human conditions.

scholarly journals Analysis of the transcriptional logic governing differential spatial expression in Hh target genes

2018 ◽  
Author(s):  
Manuel Cambón ◽  
Óscar Sánchez
Keyword(s):  
Transcription Factors ◽  
Cellular Response ◽  
Target Genes ◽  
Threshold Model ◽  
Theoretical Models ◽  
Transcriptional Responses ◽  
Cubitus Interruptus ◽  
Spatial Expression ◽  
Complex Process ◽  
Transcription Process

AbstractThis work provides theoretical tools to analyse the transcriptional effects of certain biochemical mechanisms (i.e. affinity and cooperativity) that have been proposed in previous literature to explain the differential spatial expression of Hedgehog target genes involved in Drosophila development. Specifically we have focused on the expression of decapentaplegic and patched. The transcription of these genes is believed to be controlled by opposing gradients of the activator and repressor forms of the transcription factor Cubitus interruptus (Ci). This study is based on a thermodynamic approach, which provides expression rates for these genes. These expression rates are controlled by transcription factors which are competing and cooperating for common binding sites. We have made mathematical representations of the different expression rates which depend on multiple factors and variables. The expressions obtained with the model have been refined to produce simpler equivalent formulae which allow for their mathematical analysis. Thanks to this, we can evaluate the correlation between the different interactions involved in transcription and the biological features observed at tissular level. These mathematical models can be applied to other morphogenes to help understand the complex transcriptional logic of opposing activator and repressor gradients.Author summaryMorphogenic differentiation is a complex process that involves emission, reception and cellular response to different signals. It is well known that the same morphogenic signal can give rise to different cellular transcriptional responses that usually depend, among other factors, on transcription factors. In concordance with the activator threshold model, classically it has been distinguished between high and low threshold target genes in order to explain how cells receiving the same signal can activate different genes. However, in particular cases where the transcription is controlled by two opposing transcription factors, it has been tested that this logic is not valid. This motivates the necessity for describing new theoretical models in order to understand better these cellular responses. By a theoretical analysis we have deduced different versions of transcriptional logic that are significantly determined by how the opposing transcription factors cooperate between them in the transcription process. We have also tested these different scenarios focussing on the Drosophila Hh target genes, and we have reproduced similar conclusions to the ones obtained by other methodologies.

Pirfenidone exerts anti-fibrotic effects through Inhibition of GLI transcription factors

Pneumologie ◽  
2018 ◽  
Vol 72 (S 01) ◽  
pp. S114-S115
Author(s):  
M Wygrecka ◽  
M Didiasova ◽  
R Singh ◽  
J Wilhelm ◽  
G Kwapiszewska ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Gli Transcription Factors

Astrocytes in health and disease

2007 ◽  
Vol 148 (15) ◽  
pp. 697-702 ◽  
Author(s):  
Marianna Murányi ◽  
Zsombor Lacza
Keyword(s):  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Free Radicals ◽  
Molecular Mechanisms ◽  
Neuronal Dysfunction ◽  
Supporting Cells ◽  
Neuronal Synapses ◽  
Health And Disease ◽  
Novel Targets ◽  
Therapeutic Tools

It is now known that astrocytes are not merely supporting cells but they also play an important role in neuronal funcions. Astrocytes tightly ensheat neuronal synapses and regulate the excitation of neurons by uptaking neurotransmitters; reglulate the cerebral blood flow, cerebral fluid volume and extracellular concentrations of ions. They also supply fuel in the form of lactate and provide free radical scavangers such as glutathione for active neurons. These facts indicate that impaired function of astrocytes may lead to neuronal dysfunction. After brain injury (stroke, trauma or tumors) astrocytes are swollen and release active molecules such as glutamate or free radicals resulting in neuronal dysfunction. Thus, investigation of the molecular mechanisms of astrocyte function may reveal novel targets for the development of therapeutic tools in neuronal diseases.

High Altitude hypoxia

2020 ◽  
Vol 17 ◽  
Author(s):  
Asma Babar ◽  
Kifayatullah Mengal ◽  
Abdul Hanan Babar ◽  
Shixin Wu ◽  
Mujahid Ali Shah ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
High Altitude ◽  
Molecular Mechanisms ◽  
Strong Association ◽  
Haemoglobin Concentration ◽  
Metabolic Reprogramming ◽  
Molecular Networks ◽  
Whole Genome ◽  
Gene Expressions ◽  
Transcriptional Responses

: The world highest and largest altitude area is called the Qinghai-Tibetan plateau (QTB), which harbors unique animal and plant species. Mammals that inhabit the higher altitude regions have adapted well to the hypoxic conditions. One of the main stressors at high altitude is hypoxia. Metabolic responses to hypoxia play important roles in cell survival strategies and some diseases. However, the homeostatic alterations that equilibrate variations in the demand and supply of energy to maintain organismal function in a prolonged low O2 environment persist partly understood, making it problematic to differentiate adaptive from maladaptive responses in hypoxia. Tibetans and yaks are two perfect examples innate to the plateau for high altitude adaptation. By the scan of the whole-genome, EPAS1 and EGLN1 were identified as key genes associated with sustained haemoglobin concentration in high altitude mammals for adaptation. The yak is a much more ancient mammal which has existed on QTB longer than humans, it is, therefore, possible that natural selection represented a diverse group of genes/pathways in yaks. Physiological characteristics are extremely informative in revealing molecular networks associated with inherited adaptation, in addition to the whole-genome adaptive changes at the DNA sequence level. Gene-expression can be changed by a variety of signals originating from the environment, and hypoxia is the main factor amongst them. The hypoxia-inducible factors (HIF-1α and EPAS1/HIF-2α) are the main regulators of oxygen in homeostasis which play a role as maestro regulators of adaptation in hypoxic reaction of molecular mechanisms. (Vague) The basis of this review is to present recent information regarding the molecular mechanism involved in hypoxia that regulates candidate genes and proteins. Many transcriptional responses toward hypoxia are facilitated by HIFs that change the number of gene expressions and help in angiogenesis, erythropoiesis, metabolic reprogramming and metastasis. HIFs also activate several signals highlighting a strong association between hypoxia, the misfolded proteins’ accumulation in the endoplasmic reticulum in stress and activation of unfolded protein response (UPR). It was observed that at high-altitude, pregnancies yield a low birth weight ∼100 g per1000 m of the climb. (Vague) It may involve variation in the events of energy-demanding, like protein synthesis. Prolonged hypobaric hypoxia causes placental ER stress, which in turn, moderates protein synthesis and reduces proliferation. Further, Cardiac hypertrophy by cytosolic Ca2+ raises and Ca2+/calmodulin, calcineurin stimulation, NF-AT3 pathway might be caused by an imbalance in Sarcoplasmic reticulum ER Ca2, might be adaptive in beginning but severe later.

scholarly journals DNA Methylation Profiles of Tph1A and BDNF in Gut and Brain of L. Rhamnosus-Treated Zebrafish

Biomolecules ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 142
Author(s):  
Mariella Cuomo ◽  
Luca Borrelli ◽  
Rosa Della Monica ◽  
Lorena Coretti ◽  
Giulia De Riso ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Molecular Mechanisms ◽  
The Past ◽  
Targeted Analysis ◽  
Lack Of Information ◽  
High Resolution Power ◽  
Resolution Level ◽  
Health And Disease ◽  
High Doses ◽  
The Brain

The bidirectional microbiota–gut–brain axis has raised increasing interest over the past years in the context of health and disease, but there is a lack of information on molecular mechanisms underlying this connection. We hypothesized that change in microbiota composition may affect brain epigenetics leading to long-lasting effects on specific brain gene regulation. To test this hypothesis, we used Zebrafish (Danio Rerio) as a model system. As previously shown, treatment with high doses of probiotics can modulate behavior in Zebrafish, causing significant changes in the expression of some brain-relevant genes, such as BDNF and Tph1A. Using an ultra-deep targeted analysis, we investigated the methylation state of the BDNF and Tph1A promoter region in the brain and gut of probiotic-treated and untreated Zebrafishes. Thanks to the high resolution power of our analysis, we evaluated cell-to-cell methylation differences. At this resolution level, we found slight DNA methylation changes in probiotic-treated samples, likely related to a subgroup of brain and gut cells, and that specific DNA methylation signatures significantly correlated with specific behavioral scores.

scholarly journals Circadian Blood Pressure Rhythm in Cardiovascular and Renal Health and Disease

Biomolecules ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 868
Author(s):  
Jiayang Zhang ◽  
Ruoyu Sun ◽  
Tingting Jiang ◽  
Guangrui Yang ◽  
Lihong Chen
Keyword(s):  
Blood Pressure ◽  
Circadian Rhythm ◽  
Molecular Mechanisms ◽  
Current Understanding ◽  
Renal Outcomes ◽  
Circadian Blood Pressure ◽  
Health And Disease ◽  
The Relationship

Blood pressure (BP) follows a circadian rhythm, it increases on waking in the morning and decreases during sleeping at night. Disruption of the circadian BP rhythm has been reported to be associated with worsened cardiovascular and renal outcomes, however the underlying molecular mechanisms are still not clear. In this review, we briefly summarized the current understanding of the circadian BP regulation and provided therapeutic overview of the relationship between circadian BP rhythm and cardiovascular and renal health and disease.

scholarly journals Fibrillar α-synuclein induces neurotoxic astrocyte activation via RIP kinase signaling and NF-κB

2021 ◽  
Vol 12 (8) ◽  
Author(s):  
Tsui-Wen Chou ◽  
Nydia P. Chang ◽  
Medha Krishnagiri ◽  
Aisha P. Patel ◽  
Marissa Lindman ◽  
...  
Keyword(s):  
Cell Death ◽  
Cell Biology ◽  
Molecular Mechanisms ◽  
Neurodegenerative Disorder ◽  
Neuronal Cell ◽  
Dopamine Neurons ◽  
Functional Markers ◽  
Kinase Signaling ◽  
Astrocyte Activation ◽  
Transcriptional Responses

AbstractParkinson’s disease (PD) is a neurodegenerative disorder characterized by the death of midbrain dopamine neurons. The pathogenesis of PD is poorly understood, though misfolded and/or aggregated forms of the protein α-synuclein have been implicated in several neurodegenerative disease processes, including neuroinflammation and astrocyte activation. Astrocytes in the midbrain play complex roles during PD, initiating both harmful and protective processes that vary over the course of the disease. However, despite their significant regulatory roles during neurodegeneration, the cellular and molecular mechanisms that promote pathogenic astrocyte activity remain mysterious. Here, we show that α-synuclein preformed fibrils (PFFs) induce pathogenic activation of human midbrain astrocytes, marked by inflammatory transcriptional responses, downregulation of phagocytic function, and conferral of neurotoxic activity. These effects required the necroptotic kinases RIPK1 and RIPK3, but were independent of MLKL and necroptosis. Instead, both transcriptional and functional markers of astrocyte activation occurred via RIPK-dependent activation of NF-κB signaling. Our study identifies a previously unknown function for α-synuclein in promoting neurotoxic astrocyte activation, as well as new cell death-independent roles for RIP kinase signaling in the regulation of glial cell biology and neuroinflammation. Together, these findings highlight previously unappreciated molecular mechanisms of pathologic astrocyte activation and neuronal cell death with implications for Parkinsonian neurodegeneration.

scholarly journals High Energy Intake Induced Overexpression of Transcription Factors and Its Regulatory Genes Involved in Acceleration of Hepatic Lipogenesis: A Rat Model for Type 2 Diabetes

Biomedicines ◽  
2019 ◽  
Vol 7 (4) ◽  
pp. 76 ◽  
Author(s):  
Suresh P. Khadke ◽  
Aniket A. Kuvalekar ◽  
Abhay M. Harsulkar ◽  
Nitin Mantri
Keyword(s):  
Type 2 Diabetes ◽  
Transcription Factors ◽  
Glucose Tolerance ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
High Energy ◽  
Tolerance Test ◽  
Diabetic Control ◽  
Ppar Γ

Type 2 diabetes mellitus (T2DM) is a metabolic disorder characterized by impaired insulin action and its secretion. The objectives of the present study were to establish an economical and efficient animal model, mimicking pathophysiology of human T2DM to understand probable molecular mechanisms in context with lipid metabolism. In the present study, male Wistar rats were randomly divided into three groups. Animals were fed with high fat diet (HFD) except healthy control (HC) for 12 weeks. After eight weeks, intra peritoneal glucose tolerance test was performed. After confirmation of glucose intolerance, diabetic control (DC) group was injected with streptozotocin (STZ) (35 mg/kg b.w., i.p.). HFD fed rats showed increase (p ≤ 0.001) in glucose tolerance and HOMA-IR as compared to HC. Diabetes rats showed abnormal (p ≤ 0.001) lipid profile as compared to HC. The hepatocyte expression of transcription factors SREBP-1c and NFκβ, and their target genes were found to be upregulated, while PPAR-γ, CPT1A and FABP expressions were downregulated as compared to the HC. A number of animal models have been raised for studying T2DM, but the study has been restricted to only the biochemical level. The model is validated at biochemical, molecular and histopathological levels, which can be used for screening new therapeutics for the effective management of T2DM.

scholarly journals Fuzzy modeling reveals a dynamic self-sustaining network of the GLI transcription factors controlling important metabolic regulators in adult mouse hepatocytes

2015 ◽  
Vol 11 (8) ◽  
pp. 2190-2197 ◽  
Author(s):  
Wolfgang Schmidt-Heck ◽  
Madlen Matz-Soja ◽  
Susanne Aleithe ◽  
Eugenia Marbach ◽  
Reinhard Guthke ◽  
...  
Keyword(s):  
Fuzzy Logic ◽  
Transcription Factors ◽  
Regulatory Network ◽  
Adult Mouse ◽  
Dynamic Features ◽  
Hedgehog Signalling ◽  
Gli Transcription Factors ◽  
Mouse Hepatocytes ◽  
Metabolic Regulators ◽  
Modelling Approach

The Hedgehog signalling-driven Gli transcription factors in hepatocytes form a regulatory network identified by a fuzzy-logic modelling approach. The network explains dynamic features important for hepatocyte function and fate.

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