scholarly journals TAZ Represses the Neuronal Commitment of Neural Stem Cells

Cells ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. 2230
Author(s):  
Natalia Robledinos-Antón ◽  
Maribel Escoll ◽  
Kun-Liang Guan ◽  
Antonio Cuadrado
Keyword(s):  
Neuronal Differentiation ◽  
Subventricular Zone ◽  
Transcriptional Repression ◽  
Genetic Manipulation ◽  
Mammalian Brain ◽  
Additional Function ◽  
Neural Stem Progenitor Cells ◽  
Neuronal Lineage ◽  
Neuronal Commitment

The mechanisms involved in regulation of quiescence, proliferation, and reprogramming of Neural Stem Progenitor Cells (NSPCs) of the mammalian brain are still poorly defined. Here, we studied the role of the transcriptional co-factor TAZ, regulated by the WNT and Hippo pathways, in the homeostasis of NSPCs. We found that, in the murine neurogenic niches of the striatal subventricular zone and the dentate gyrus granular zone, TAZ is highly expressed in NSPCs and declines with ageing. Moreover, TAZ expression is lost in immature neurons of both neurogenic regions. To characterize mechanistically the role of TAZ in neuronal differentiation, we used the midbrain-derived NSPC line ReNcell VM to replicate in a non-animal model the factors influencing NSPC differentiation to the neuronal lineage. TAZ knock-down and forced expression in NSPCs led to increased and reduced neuronal differentiation, respectively. TEADs-knockdown indicated that these TAZ co-partners are required for the suppression of NSPCs commitment to neuronal differentiation. Genetic manipulation of the TAZ/TEAD system showed its participation in transcriptional repression of SOX2 and the proneuronal genes ASCL1, NEUROG2, and NEUROD1, leading to impediment of neurogenesis. TAZ is usually considered a transcriptional co-activator promoting stem cell proliferation, but our study indicates an additional function as a repressor of neuronal differentiation.

scholarly journals Role of Nox4 in Neuronal Differentiation of Mouse Subventricular Zone Neural Stem Cells

2016 ◽  
Vol 26 (1) ◽  
pp. 8-16 ◽  
Author(s):  
Ki-Youb Park ◽  
Yerin Na ◽  
Man Su Kim
Keyword(s):  
Stem Cells ◽  
Neural Stem Cells ◽  
Neuronal Differentiation ◽  
Subventricular Zone

scholarly journals FBXL5 Inactivation in Mouse Brain Induces Aberrant Proliferation of Neural Stem Progenitor Cells

2017 ◽  
Vol 37 (8) ◽  
Author(s):  
Takayoshi Yamauchi ◽  
Masaaki Nishiyama ◽  
Toshiro Moroishi ◽  
Atsuki Kawamura ◽  
Keiichi I. Nakayama
Keyword(s):  
Brain Development ◽  
Progenitor Cells ◽  
Mammalian Cells ◽  
Regulatory Protein ◽  
Mammalian Target Of Rapamycin ◽  
Progressive Increase ◽  
Mammalian Brain ◽  
Intracellular Iron ◽  
Neural Stem Progenitor Cells

ABSTRACT FBXL5 is the substrate recognition subunit of an SCF-type ubiquitin ligase that serves as a master regulator of iron metabolism in mammalian cells. We previously showed that mice with systemic deficiency of FBXL5 fail to sense intracellular iron levels and die in utero at embryonic day 8.5 (E8.5) as a result of iron overload and subsequent oxidative stress. This early embryonic mortality has thus impeded study of the role of FBXL5 in brain development. We have now generated mice lacking FBXL5 specifically in nestin-expressing neural stem progenitor cells (NSPCs) in the brain. Unexpectedly, the mutant embryos manifested a progressive increase in the number of NSPCs and astroglia in the cerebral cortex. Stabilization of iron regulatory protein 2 (IRP2) as a result of FBXL5 deficiency led to accumulation of ferrous and ferric iron as well as to generation of reactive oxygen species. Pharmacological manipulation suggested that the phenotypes of FBXL5 deficiency are attributable to aberrant activation of mammalian target of rapamycin (mTOR) signaling. Our results thus show that FBXL5 contributes to regulation of NSPC proliferation during mammalian brain development.

scholarly journals Histone Methylations Define Neural Stem/Progenitor Cell Subtypes in the Mouse Subventricular Zone

2019 ◽  
Vol 57 (2) ◽  
pp. 997-1008 ◽  
Author(s):  
Zhichao Zhang ◽  
Adeel Manaf ◽  
Yanjiao Li ◽  
Sonia Peña Perez ◽  
Rajikala Suganthan ◽  
...  
Keyword(s):  
Subventricular Zone ◽  
Progenitor Cell ◽  
Individual Cell ◽  
Histone H3 ◽  
Cell Types ◽  
Mammalian Brain ◽  
Neural Stem Progenitor Cells ◽  
Neurologic Function ◽  
Novel Strategy ◽  
The Brain

Abstract Neural stem/progenitor cells (NSPCs) persist in the mammalian brain throughout life and can be activated in response to the physiological and pathophysiological stimuli. Epigenetic reprogramming of NPSC represents a novel strategy for enhancing the intrinsic potential of the brain to regenerate after brain injury. Therefore, defining the epigenetic features of NSPCs is important for developing epigenetic therapies for targeted reprogramming of NSPCs to rescue neurologic function after injury. In this study, we aimed at defining different subtypes of NSPCs by individual histone methylations. We found the three histone marks, histone H3 lysine 4 trimethylation (H3K4me3), histone H3 lysine 27 trimethylation (H3K27me3), and histone H3 lysine 36 trimethylation (H3K36me3), to nicely and dynamically portray individual cell types during neurodevelopment. First, we found all three marks co-stained with NSPC marker SOX2 in mouse subventricular zone. Then, CD133, Id1, Mash1, and DCX immunostaining were used to define NSPC subtypes. Type E/B, B/C, and C/A cells showed high levels of H3K27me3, H3K36me3, and H3K4me3, respectively. Our results reveal defined histone methylations of NSPC subtypes supporting that epigenetic regulation is critical for neurogenesis and for maintaining NSPCs.

scholarly journals Identification of the Sin3-Binding Site in Ume6 Defines a Two-Step Process for Conversion of Ume6 from a Transcriptional Repressor to an Activator in Yeast

2001 ◽  
Vol 21 (6) ◽  
pp. 2057-2069 ◽  
Author(s):  
Brian K. Washburn ◽  
Rochelle Easton Esposito
Keyword(s):  
Transcriptional Repression ◽  
Hormone Receptors ◽  
Alpha Helix ◽  
Activation Domain ◽  
Additional Function ◽  
Meiotic Progression ◽  
Regulatory Complex ◽  
Amphipathic Alpha Helix ◽  
Two Hybrid

ABSTRACT The DNA-binding protein Ume6 is required for both repression and activation of meiosis-specific genes, through interaction with the Sin3 corepressor and Rpd3 histone deacetylase and the meiotic activator Ime1. Here we show that fusion of a heterologous activation domain to Ume6 is unable to convert it into a constitutive activator of early meiotic gene transcription, indicating that an additional function is needed to overcome repression at these promoters. Mutations in UME6 allowing the fusion to activate lie in a predicted amphipathic alpha helix and specifically disrupt interaction with Sin3 but not with Teal, an activator of Ty transcription also found to interact with Ume6 in a two-hybrid screen. The mutations cause a loss of repression by Ume6 and precisely identify the Ume6 Sin3-binding domain, which we show interacts with the paired amphipathic helix 2 region of Sin3. Analysis of these mutants indicates that conversion of Ume6 to an activator involves two genetically distinct steps that act to relieve Sin3-mediated repression and provide an activation domain to Ume6. The mutants further demonstrate that premature expression and lack of subsequent rerepression of Ume6-Sin3-regulated genes are not deleterious to meiotic progression and suggest that the essential role of Sin3 in meiosis is independent of Ume6. The model for Ume6 function arising from these studies indicates that Ume6 is similar in many respects to metazoan regulators that utilize Sin3, such as the Myc-Mad-Max system and nuclear hormone receptors, and provides new insights into the control of transcriptional repression and activation by the Ume6-URS1 regulatory complex in yeast.

scholarly journals CIC is a Critical Regulator of Neuronal Differentiation

2019 ◽  
Author(s):  
Inah Hwang ◽  
Heng Pan ◽  
Jun Yao ◽  
Olivier Elemento ◽  
Hongwu Zheng ◽  
...  
Keyword(s):  
Neuronal Differentiation ◽  
Transcriptional Repression ◽  
High Mobility ◽  
Neural Progenitor Cell ◽  
Mass Spectrometry Analysis ◽  
Transcriptional Repressors ◽  
Spectrometry Analysis ◽  
Corepressor Complex ◽  
Progenitor Cell Proliferation ◽  
Neuronal Lineage

ABSTRACTCapicua (CIC), a member of the high mobility group (HMG)-box superfamily of transcriptional repressors, is frequently mutated in human oligodendrogliomas. But its function in brain development and tumorigenesis remains poorly understood. Here, we report that brain-specific deletion of Cic compromises developmental transition of neuroblast to immature neurons in mouse hippocampus and compromises normal neuronal differentiation. Combined gene expression and ChIP-seq analyses identified VGF as an important CIC-repressed transcriptional surrogates involved in neuronal lineage regulation. Aberrant VGF expression promotes neural progenitor cell proliferation by suppressing their differentiation. Mechanistically, we demonstrated that CIC represses VGF expression by tethering SIN3-HDAC to form a transcriptional corepressor complex. Mass spectrometry analysis of CIC-interacting proteins further identified BRG1 containing mSWI/SNF complex of which function is necessary for transcriptional repression by CIC. Together, this study uncovers a novel regulatory pathway of CIC-dependent neuronal differentiation and provides molecular insights into the etiology of CIC-dependent brain tumors.

scholarly journals Phosphorylation of GAPVD1 Is Regulated by the PER Complex and Linked to GAPVD1 Degradation

2021 ◽  
Vol 22 (7) ◽  
pp. 3787
Author(s):  
Hussam Ibrahim ◽  
Philipp Reus ◽  
Anna Katharina Mundorf ◽  
Anna-Lena Grothoff ◽  
Valerie Rudenko ◽  
...  
Keyword(s):  
Circadian Clock ◽  
Transcriptional Repression ◽  
Small Gtpase ◽  
Main Role ◽  
Interacting Proteins ◽  
Casein Kinase 1 ◽  
Bona Fide ◽  
Kinetics Of

Repressor protein period (PER) complexes play a central role in the molecular oscillator mechanism of the mammalian circadian clock. While the main role of nuclear PER complexes is transcriptional repression, much less is known about the functions of cytoplasmic PER complexes. We found with a biochemical screen for PER2-interacting proteins that the small GTPase regulator GTPase-activating protein and VPS9 domain-containing protein 1 (GAPVD1), which has been identified previously as a component of cytoplasmic PER complexes in mice, is also a bona fide component of human PER complexes. We show that in situ GAPVD1 is closely associated with casein kinase 1 delta (CSNK1D), a kinase that regulates PER2 levels through a phosphoswitch mechanism, and that CSNK1D regulates the phosphorylation of GAPVD1. Moreover, phosphorylation determines the kinetics of GAPVD1 degradation and is controlled by PER2 and a C-terminal autoinhibitory domain in CSNK1D, indicating that the regulation of GAPVD1 phosphorylation is a novel function of cytoplasmic PER complexes and might be part of the oscillator mechanism or an output function of the circadian clock.

scholarly journals Genetic Analysis of the Role of Pol II Holoenzyme Components in Repression by the Cyc8-Tup1 Corepressor in Yeast

Genetics ◽  
2000 ◽  
Vol 155 (4) ◽  
pp. 1535-1542 ◽  
Author(s):  
Mark Lee ◽  
Sukalyan Chatterjee ◽  
Kevin Struhl
Keyword(s):  
Transcriptional Repression ◽  
Detectable Effect ◽  
Genetic Screens ◽  
Phenotypic Analysis ◽  
Histone Tails ◽  
Pol Ii ◽  
Corepressor Complex ◽  
The Individual ◽  
Modest Effect

Abstract The Cyc8-Tup1 corepressor complex is targeted to promoters by pathway-specific DNA-binding repressors, thereby inhibiting the transcription of specific classes of genes. Genetic screens have identified mutations in a variety of Pol II holoenzyme components (Srb8, Srb9, Srb10, Srb11, Sin4, Rgr1, Rox3, and Hrs1) and in the N-terminal tails of histones H3 and H4 that weaken repression by Cyc8-Tup1. Here, we analyze the effect of individual and multiple mutations in many of these components on transcriptional repression of natural promoters that are regulated by Cyc8-Tup1. In all cases tested, individual mutations have a very modest effect on SUC2 RNA levels and no detectable effect on levels of ANB1, MFA2, and RNR2. Furthermore, multiple mutations within the Srb components, between Srbs and Sin4, and between Srbs and histone tails affect Cyc8-Tup1 repression to the same modest extent as the individual mutations. These results argue that the weak effects of the various mutations on repression by Cyc8-Tup1 are not due to redundancy among components of the Pol II machinery, and they argue against a simple redundancy between the holoenzyme and chromatin pathways. In addition, phenotypic analysis indicates that, although Srbs8–11 are indistinguishable with respect to Cyc8-Tup1 repression, the individual Srbs are functionally distinct in other respects. Genetic interactions among srb mutations imply that a balance between the activities of Srb8 + Srb10 and Srb11 is important for normal cell growth.

scholarly journals Cytosolic Ribosomal Mutations That Abolish Accumulation of Circular Intron in the Mitochondria Without Preventing Senescence of Podospora anserina

Genetics ◽  
1997 ◽  
Vol 145 (3) ◽  
pp. 697-705 ◽  
Author(s):  
Philippe Silar ◽  
France Koll ◽  
Michèle Rossignol
Keyword(s):  
Mitochondrial Dna ◽  
Ribosomal Proteins ◽  
Podospora Anserina ◽  
Cox1 Gene ◽  
Accuracy Control ◽  
Additional Function ◽  
Mutant Proteins ◽  
Double Stranded Dna ◽  
Dna Modifications

The filamentous fungus Podospora anserina presents a degeneration syndrome called Senescence associated with mitochondrial DNA modifications. We show that mutations affecting the two different and interacting cytosolic ribosomal proteins (S7 and S19) systematically and specifically prevent the accumulation of senDNAα (a circular double-stranded DNA plasmid derived from the first intron of the mitochondrial cox1 gene or intron α) without abolishing Senescence nor affecting the accumulation of other usually observed mitochondrial DNA rearrangements. One of the mutant proteins is homologous to the Escherichia coli S4 and Saccharomyces cerevisiae S13 ribosomal proteins, known to be involved in accuracy control of cytosolic translation. The lack of accumulation of senDNAα seems to result from a nontrivial ribosomal alteration unrelated to accuracy control, indicating that S7 and S19 proteins have an additional function. The results strongly suggest that modified expression of nucleus-encoded proteins contributes to Senescence in P. anserina. These data do not fit well with some current models, which propose that intron α plays the role of the cytoplasmic and infectious Determinant of Senescence that was defined in early studies.

scholarly journals Tcf4 Is Involved in Subset Specification of Mesodiencephalic Dopaminergic Neurons

Biomedicines ◽  
2021 ◽  
Vol 9 (3) ◽  
pp. 317
Author(s):  
Simone Mesman ◽  
Iris Wever ◽  
Marten P. Smidt
Keyword(s):  
Neuronal Differentiation ◽  
Dopaminergic Neurons ◽  
Neuronal Development ◽  
Neuronal Population ◽  
Minor Role ◽  
Initial Increase ◽  
E Box ◽  
A Minor ◽  
Bhlh Factor

During development, mesodiencephalic dopaminergic (mdDA) neurons form into different molecular subsets. Knowledge of which factors contribute to the specification of these subsets is currently insufficient. In this study, we examined the role of Tcf4, a member of the E-box protein family, in mdDA neuronal development and subset specification. We show that Tcf4 is expressed throughout development, but is no longer detected in adult midbrain. Deletion of Tcf4 results in an initial increase in TH-expressing neurons at E11.5, but this normalizes at later embryonic stages. However, the caudal subset marker Nxph3 and rostral subset marker Ahd2 are affected at E14.5, indicating that Tcf4 is involved in correct differentiation of mdDA neuronal subsets. At P0, expression of these markers partially recovers, whereas expression of Th transcript and TH protein appears to be affected in lateral parts of the mdDA neuronal population. The initial increase in TH-expressing cells and delay in subset specification could be due to the increase in expression of the bHLH factor Ascl1, known for its role in mdDA neuronal differentiation, upon loss of Tcf4. Taken together, our data identified a minor role for Tcf4 in mdDA neuronal development and subset specification.

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