scholarly journals Disruption of CK2β in Embryonic Neural Stem Cells Compromises Proliferation and Oligodendrogenesis in the Mouse Telencephalon

2010 ◽  
Vol 30 (11) ◽  
pp. 2737-2749 ◽  
Author(s):  
Emmanuelle Huillard ◽  
Léa Ziercher ◽  
Olivier Blond ◽  
Michael Wong ◽  
Jean-Christophe Deloulme ◽  
...  
Keyword(s):  
Transcription Factor ◽  
System Development ◽  
Nervous System Development ◽  
Conditional Knockout ◽  
Regulatory Subunit ◽  
Bhlh Transcription Factor ◽  
Helix Loop Helix ◽  
Proliferation And Differentiation

ABSTRACT Genetic programs that govern neural stem/progenitor cell (NSC) proliferation and differentiation are dependent on extracellular cues and a network of transcription factors, which can be regulated posttranslationally by phosphorylation. However, little is known about the kinase-dependent pathways regulating NSC maintenance and oligodendrocyte development. We used a conditional knockout approach to target the murine regulatory subunit (beta) of protein kinase casein kinase 2 (CK2β) in embryonic neural progenitors. Loss of CK2β leads to defects in proliferation and differentiation of embryonic NSCs. We establish CK2β as a key positive regulator for the development of oligodendrocyte precursor cells (OPCs), both in vivo and in vitro. We show that CK2β directly interacts with the basic helix-loop-helix (bHLH) transcription factor Olig2, a critical modulator of OPC development, and activates the CK2-dependent phosphorylation of its serine-threonine-rich (STR) domain. Finally, we reveal that the CK2-targeted STR domain is required for the oligodendroglial function of Olig2. These findings suggest that CK2 may control oligodendrogenesis, in part, by regulating the activity of the lineage-specific transcription factor Olig2. Thus, CK2β appears to play an essential and uncompensated role in central nervous system development.

scholarly journals Id Helix-Loop-Helix Proteins Antagonize Pax Transcription Factor Activity by Inhibiting DNA Binding

2001 ◽  
Vol 21 (2) ◽  
pp. 524-533 ◽  
Author(s):  
E. Claire Roberts ◽  
Richard W. Deed ◽  
Toshiaki Inoue ◽  
John D. Norton ◽  
Andrew D. Sharrocks
Keyword(s):  
Transcription Factor ◽  
Dna Binding ◽  
Cellular Proliferation ◽  
Regulatory Function ◽  
Transcription Factor Family ◽  
Helix Loop Helix ◽  
Id Proteins ◽  
Proliferation And Differentiation

ABSTRACT The Id subfamily of helix-loop-helix (HLH) proteins plays a fundamental role in the regulation of cellular proliferation and differentiation. The major mechanism by which Id proteins are thought to inhibit differentiation is through interaction with other HLH proteins and inhibition of their DNA-binding activity. However, Id proteins have also been shown to interact with other proteins involved in regulating cellular proliferation and differentiation, suggesting a more widespread regulatory function. In this study we demonstrate functional interactions between Id proteins and members of the Pax-2/-5/-8 subfamily of paired-domain transcription factors. Members of the Pax transcription factor family have key functions in regulating several developmental processes exemplified by B lymphopoiesis, in which Pax-5 plays an essential role. Id proteins bind to Pax proteins in vitro and in vivo. Binding occurs through the paired DNA-binding domain of the Pax proteins and results in the disruption of DNA-bound complexes containing Pax-2, Pax-5, and Pax-8. In vivo, Id proteins modulate the transcriptional activity mediated by Pax-5 complexes on the B-cell-specific mb-1 promoter. Our results therefore demonstrate a novel facet of Id function in regulating cellular differentiation by functionally antagonizing the action of members of the Pax transcription factor family.

scholarly journals The N terminus of Ascl1 underlies differing proneural activity of mouse and Xenopus Ascl1 proteins

2018 ◽  
Vol 3 ◽  
pp. 125 ◽  
Author(s):  
Laura J.A. Hardwick ◽  
Anna Philpott
Keyword(s):  
Transcription Factor ◽  
Bhlh Transcription Factor ◽  
Protein Accumulation ◽  
Primary Neuron ◽  
Helix Loop Helix ◽  
N Terminus ◽  
Specific Regulation ◽  
Species Specific

The proneural basic-helix-loop-helix (bHLH) transcription factor Ascl1 is a master regulator of neurogenesis in both central and peripheral nervous systems in vivo, and is a central driver of neuronal reprogramming in vitro. Over the last three decades, assaying primary neuron formation in Xenopus embryos in response to transcription factor overexpression has contributed to our understanding of the roles and regulation of proneural proteins like Ascl1, with homologues from different species usually exhibiting similar functional effects. Here we demonstrate that the mouse Ascl1 protein is twice as active as the Xenopus protein in inducing neural-β-tubulin expression in Xenopus embryos, despite there being little difference in protein accumulation or ability to undergo phosphorylation, two properties known to influence Ascl1 function. This superior activity of the mouse compared to the Xenopus protein is dependent on the presence of the non-conserved N terminal region of the protein, and indicates species-specific regulation that may necessitate care when interpreting results in cross-species experiments.

scholarly journals Drosophila Stathmin: A Microtubule-destabilizing Factor Involved in Nervous System Formation

2002 ◽  
Vol 13 (2) ◽  
pp. 698-710 ◽  
Author(s):  
Sylvie Ozon ◽  
Antoine Guichet ◽  
Olivier Gavet ◽  
Siegfried Roth ◽  
André Sobel
Keyword(s):  
Nervous System ◽  
System Development ◽  
Nervous System Development ◽  
Microtubule Assembly ◽  
Nervous Systems ◽  
Germ Cell Migration ◽  
Numerous Cell ◽  
First Time

Stathmin is a ubiquitous regulatory phosphoprotein, the generic element of a family of neural phosphoproteins in vertebrates that possess the capacity to bind tubulin and interfere with microtubule dynamics. Although stathmin and the other proteins of the family have been associated with numerous cell regulations, their biological roles remain elusive, as in particular inactivation of the stathmin gene in the mouse resulted in no clear deleterious phenotype. We identified stathmin phosphoproteins inDrosophila, encoded by a unique gene sharing the intron/exon structure of the vertebrate stathmin andstathmin family genes. They interfere with microtubule assembly in vitro, and in vivo when expressed in HeLa cells. Drosophila stathmin expression is regulated during embryogenesis: it is high in the migrating germ cells and in the central and peripheral nervous systems, a pattern resembling that of mammalian stathmin. Furthermore, RNA interference inactivation ofDrosophila stathmin expression resulted in germ cell migration arrest at stage 14. It also induced important anomalies in nervous system development, such as loss of commissures and longitudinal connectives in the ventral cord, or abnormal chordotonal neuron organization. In conclusion, a single Drosophilagene encodes phosphoproteins homologous to the entire vertebrate stathmin family. We demonstrate for the first time their direct involvement in major biological processes such as development of the reproductive and nervous systems.

The basic helix-loop-helix transcription factor bHLH95 affects fruit ripening and multiple metabolisms in tomato

2020 ◽  
Vol 71 (20) ◽  
pp. 6311-6327
Author(s):  
Lincheng Zhang ◽  
Jing Kang ◽  
Qiaoli Xie ◽  
Jun Gong ◽  
Hui Shen ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Fruit Ripening ◽  
Tomato Fruit ◽  
Soluble Sugar ◽  
Glutathione Metabolism ◽  
Bhlh Transcription Factor ◽  
Total Carotenoids ◽  
Helix Loop Helix ◽  
Tomato Fruit Ripening

Abstract Ethylene signaling pathways regulate several physiological alterations that occur during tomato fruit ripening, such as changes in colour and flavour. The mechanisms underlying the transcriptional regulation of genes in these pathways remain unclear, although the role of the MADS-box transcription factor RIN has been widely reported. Here, we describe a bHLH transcription factor, SlbHLH95, whose transcripts accumulated abundantly in breaker+4 and breaker+7 fruits compared with rin (ripening inhibitor) and Nr (never ripe) mutants. Moreover, the promoter activity of SlbHLH95 was regulated by RIN in vivo. Suppression of SlbHLH95 resulted in reduced sensitivity to ethylene, decreased accumulation of total carotenoids, and lowered glutathione content, and inhibited the expression of fruit ripening- and glutathione metabolism-related genes. Conversely, up-regulation of SlbHLH95 in wild-type tomato resulted in higher sensitivity to ethylene, increased accumulation of total carotenoids, slightly premature ripening, and elevated accumulation of glutathione, soluble sugar, and starch. Notably, overexpression of SlbHLH95 in rin led to the up-regulated expression of fruit ripening-related genes (FUL1, FUL2, SAUR69, ERF4, and CNR) and multiple glutathione metabolism-related genes (GSH1, GSH2, GSTF1, and GSTF5). These results clarified that SlbHLH95 participates in the regulation of fruit ripening and affects ethylene sensitivity and multiple metabolisms targeted by RIN in tomato.

scholarly journals Laminar specific attachment and neurite outgrowth of thalamic neurons on cultured slices of developing cerebral neocortex

Development ◽  
1994 ◽  
Vol 120 (10) ◽  
pp. 2811-2822 ◽  
Author(s):  
D.E. Emerling ◽  
A.D. Lander
Keyword(s):  
Cell Attachment ◽  
System Development ◽  
Nervous System Development ◽  
Cortical Plate ◽  
Spatial Patterning ◽  
Extracellular Matrix Molecules ◽  
Process Outgrowth ◽  
Cultured Slices

In nervous system development, the growth cones of advancing axons are thought to navigate to their targets by recognizing cell-surface and extracellular matrix molecules that act as specific guidance cues. To identify and map cues that guide the growth of a particular axonal system, the thalamocortical afferents, an assay was devised to examine short-term interactions of dissociated embryonic thalamic cells with living, approximately 150 microns slices of developing mouse forebrain. Thalamic cells rapidly (< 3 hours) and efficiently attached to and extended neurites on pre- and postnatal slices, but a broad zone throughout the neocortex was generally non-permissive for both thalamic cell attachment and the ingrowth of neurites. This zone coincided with the cortical plate at early stages (embryonic day 15), but later became restricted, in rostral-to-caudal fashion, to cortical laminae 2/3. Thus, at each stage, thalamic cells in vitro avoided just that area that thalamic axons confront, but generally do not enter, in vivo. In addition, neurites that extended on some layers were found to be significantly oriented in directions that coincide with the pathways that thalamic axons follow in vivo. These results imply that local adhesive cues and signals that affect process outgrowth are distributed among developing cortical laminae in a manner that could underlie much of the temporal and spatial patterning of thalamocortical innervation.

Dynamic effects of Fto in regulating the proliferation and differentiation of adult neural stem cells of mice

2019 ◽  
Vol 29 (5) ◽  
pp. 727-735 ◽  
Author(s):  
Yuhang Cao ◽  
Yingliang Zhuang ◽  
Junchen Chen ◽  
Weize Xu ◽  
Yikai Shou ◽  
...  
Keyword(s):  
Stem Cells ◽  
Neural Stem Cells ◽  
Neuronal Development ◽  
Conditional Knockout ◽  
Biological Processes ◽  
Adult Neural Stem Cells ◽  
Proliferation And Differentiation

Abstract N 6-methyladenosine (m6A) modification of RNA is deposited by the methyltransferase complex consisting of Mettl3 and Mettl14 and erased by demethylase Fto and Alkbh5 and is involved in diverse biological processes. However, it remains largely unknown the specific function and mechanism of Fto in regulating adult neural stem cells (aNSCs). In the present study, utilizing a conditional knockout (cKO) mouse model, we show that the specific ablation of Fto in aNSCs transiently increases the proliferation of aNSCs and promotes neuronal differentiation both in vitro and in vivo, but in a long term, the specific ablation of Fto inhibits adult neurogenesis and neuronal development. Mechanistically, Fto deficiency results in a significant increase in m6A modification in Pdgfra and Socs5. The increased expression of Pdgfra and decreased expression of Socs5 synergistically promote the phosphorylation of Stat3. The modulation of Pdgfra and Socs5 can rescue the neurogenic deficits induced by Fto depletion. Our results together reveal an important function of Fto in regulating aNSCs through modulating Pdgfra/Socs5-Stat3 pathway.

scholarly journals Molecular and Cellular Function of Transcription Factor 4 in Pitt-Hopkins Syndrome

2021 ◽  
pp. 1-9
Author(s):  
Huei-Ying Chen ◽  
Joseph F. Bohlen ◽  
Brady J. Maher
Keyword(s):  
Transcription Factor ◽  
Regulatory Networks ◽  
Autosomal Dominant ◽  
Autism Spectrum ◽  
Therapeutic Interventions ◽  
Type I ◽  
Helix Loop Helix ◽  
Transcription Factor 4

Transcription factor 4 (TCF4, also known as ITF2 or E2-2) is a type I basic helix-loop-helix transcription factor. Autosomal dominant mutations in TCF4 cause Pitt-Hopkins syndrome (PTHS), a rare syndromic form of autism spectrum disorder. In this review, we provide an update on the progress regarding our understanding of TCF4 function at the molecular, cellular, physiological, and behavioral levels with a focus on phenotypes and therapeutic interventions. We examine upstream and downstream regulatory networks associated with TCF4 and discuss a range of in vitro and in vivo data with the aim of understanding emerging TCF4-specific mechanisms relevant for disease pathophysiology. In conclusion, we provide comments about exciting future avenues of research that may provide insights into potential new therapeutic targets for PTHS.

The basic-helix-loop-helix protein pod1 is critically important for kidney and lung organogenesis

Development ◽  
1999 ◽  
Vol 126 (24) ◽  
pp. 5771-5783 ◽  
Author(s):  
S.E. Quaggin ◽  
L. Schwartz ◽  
S. Cui ◽  
P. Igarashi ◽  
J. Deimling ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Molecular Mechanisms ◽  
Cell Types ◽  
Perinatal Period ◽  
Branching Morphogenesis ◽  
Bhlh Transcription Factor ◽  
Basic Helix Loop Helix ◽  
Helix Loop Helix ◽  
Kidney Morphogenesis

Epithelial-mesenchymal interactions are required for the development of all solid organs but few molecular mechanisms that underlie these interactions have been identified. Pod1 is a basic-helix-loop-helix (bHLH) transcription factor that is highly expressed in the mesenchyme of developing organs that include the lung, kidney, gut and heart and in glomerular visceral epithelial cells (podocytes). To determine the function of Pod1 in vivo, we have generated a lacZ-expressing null Pod1 allele. Null mutant mice are born but die in the perinatal period with severely hypoplastic lungs and kidneys that lack alveoli and mature glomeruli. Although Pod1 is exclusively expressed in the mesenchyme and podocytes, major defects are observed in the adjacent epithelia and include abnormalities in epithelial differentiation and branching morphogenesis. Pod1 therefore appears to be essential for regulating properties of the mesenchyme that are critically important for lung and kidney morphogenesis. Defects specific to later specialized cell types where Pod1 is expressed, such as the podocytes, were also observed, suggesting that this transcription factor may play multiple roles in kidney morphogenesis.

scholarly journals The autism and schizophrenia associated gene CYFIP1 is critical for the maintenance of dendritic complexity and the stabilization of mature spines

2014 ◽  
Vol 4 (3) ◽  
pp. e374-e374 ◽  
Author(s):  
M Pathania ◽  
E C Davenport ◽  
J Muir ◽  
D F Sheehan ◽  
G López-Doménech ◽  
...  
Keyword(s):  
Ampa Receptor ◽  
System Development ◽  
Significant Risk ◽  
Autism Spectrum ◽  
Nervous System Development ◽  
Actin Dynamics ◽  
Expression Levels ◽  
Dendritic Complexity

Abstract Copy number variation (CNV) at the 15q11.2 region has been identified as a significant risk locus for neurological and neuropsychiatric conditions such as schizophrenia (SCZ) and autism spectrum disorder (ASD). However, the individual roles for genes at this locus in nervous system development, function and connectivity remain poorly understood. Haploinsufficiency of one gene in this region, Cyfip1, may provide a model for 15q11.2 CNV-associated neuropsychiatric phenotypes. Here we show that altering CYFIP1 expression levels in neurons both in vitro and in vivo influences dendritic complexity, spine morphology, spine actin dynamics and synaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor lateral diffusion. CYFIP1 is highly enriched at synapses and its overexpression in vitro leads to increased dendritic complexity. Neurons derived from Cyfip1 heterozygous animals on the other hand, possess reduced dendritic complexity, increased mobile F-actin and enhanced GluA2-containing AMPA receptor mobility at synapses. Interestingly, Cyfip1 overexpression or haploinsufficiency increased immature spine number, whereas activity-dependent changes in spine volume were occluded in Cyfip1 haploinsufficient neurons. In vivo, Cyfip1 heterozygous animals exhibited deficits in dendritic complexity as well as an altered ratio of immature-to-mature spines in hippocampal CA1 neurons. In summary, we provide evidence that dysregulation of CYFIP1 expression levels leads to pathological changes in CNS maturation and neuronal connectivity, both of which may contribute to the development of the neurological symptoms seen in ASD and SCZ.

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