A role for neural determination genes in specifying the dorsoventral identity of telencephalic neurons

Neurogenin1 (Ngn1), Neurogenin2(Ngn2), and Mash1 encode bHLH transcription factors with neuronal determination functions. In the telencephalon, theNgns and Mash1 are expressed at high levels in complementary dorsal and ventral domains, respectively. We found thatNgn function is required to maintain these two separate expression domains, as Mash1 expression is up-regulated in the dorsal telencephalon of Ngn mutant embryos. We have taken advantage of the replacement of the Ngns by Mash1 in dorsal progenitors to address the role of the neural determination genes in neuronal-type specification in the telencephalon. InNgn2 single and Ngn1; Ngn2 double mutants, a population of early born cortical neurons lose expression of dorsal-specific markers and ectopically express a subset of ventral telencephalic-specific markers. Analysis of Mash1; Ngn2double mutant embryos and of embryos carrying a Ngn2 toMash1 replacement mutation demonstrated that ectopic expression of Mash1 is required and sufficient to confer these ventral characteristics to cortical neurons. Our results indicate that in addition to acting as neuronal determinants, Mash1 andNgns play a role in the specification of dorsal-ventral neuronal identity, directly linking pathways of neurogenesis and regional patterning in the forebrain.

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Glutathione regulates subcellular iron homeostasis via transcriptional activation of iron responsive genes in Arabidopsis

10.1101/2021.05.09.443283 ◽

2021 ◽

Author(s):

Ranjana Shee ◽

Soumi Ghosh ◽

Pinki Khan ◽

Salman Sahid ◽

Chandan Roy ◽

...

Keyword(s):

Transcription Factors ◽

Transcriptional Activation ◽

Iron Homeostasis ◽

Fe Deficiency ◽

Fe Content ◽

Increased Sensitivity ◽

Fe Homeostasis ◽

Bhlh Transcription Factors ◽

Dependent Pathway

Glutathione (GSH) is a ubiquitous molecule known to regulate various physiological and developmental phenomena in plants. Recently, its involvement in regulating iron (Fe) deficiency response was established in Arabidopsis. However, the role of GSH in modulating subcellular Fe homeostasis remained elusive. In this study, we dissected the role of GSH in regulating Fe homeostasis in Arabidopsis shoots under Fe limited conditions. The two GSH depleted mutants, cad2-1 and pad2-1 displayed increased sensitivity to Fe deficiency with smaller rosette diameter and higher chlorosis level compared with the Col-0 plants. Interestingly, the expression of the vacuolar Fe exporters, AtNRAMP3 and AtNRAMP4, chloroplast Fe importer, AtPIC1, along with AtFer1 and AtIRT1 were significantly down-regulated in these mutants. The expression of these genes were up-regulated in response to exogenous GSH treatment while treatment with BSO, a GSH inhibitor, down-regulated their expression. Moreover, the mutants accumulated higher Fe content in the vacuole and lower in the chloroplast compared with Col-0 under Fe limited condition suggesting a role of GSH in modulating subcellular Fe homeostasis. This regulation was, further, found to involve a GSNO-dependent pathway. Promoter analysis revealed that GSH induced the transcription of these genes presumably via S-nitrosylation of different Fe responsive bHLH transcription factors.

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ZNF281 inhibits neuronal differentiation and is a prognostic marker for neuroblastoma

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1801435115 ◽

2018 ◽

Vol 115 (28) ◽

pp. 7356-7361 ◽

Cited By ~ 17

Author(s):

Marco Pieraccioli ◽

Sara Nicolai ◽

Consuelo Pitolli ◽

Massimiliano Agostini ◽

Alexey Antonov ◽

...

Keyword(s):

Neuronal Differentiation ◽

Prognostic Marker ◽

Cortical Neurons ◽

Ectopic Expression ◽

Bioinformatic Analysis ◽

Cellular Processes ◽

Stage 4 ◽

Stage 1 ◽

Inappropriate Expression

Derangement of cellular differentiation because of mutation or inappropriate expression of specific genes is a common feature in tumors. Here, we show that the expression of ZNF281, a zinc finger factor involved in several cellular processes, decreases during terminal differentiation of murine cortical neurons and in retinoic acid-induced differentiation of neuroblastoma (NB) cells. The ectopic expression of ZNF281 inhibits the neuronal differentiation of murine cortical neurons and NB cells, whereas its silencing causes the opposite effect. Furthermore, TAp73 inhibits the expression of ZNF281 through miR34a. Conversely, MYCN promotes the expression of ZNF281 at least in part by inhibiting miR34a. These findings imply a functional network that includes p73, MYCN, and ZNF281 in NB cells, where ZNF281 acts by negatively affecting neuronal differentiation. Array analysis of NB cells silenced for ZNF281 expression identified GDNF and NRP2 as two transcriptional targets inhibited by ZNF281. Binding of ZNF281 to the promoters of these genes suggests a direct mechanism of repression. Bioinformatic analysis of NB datasets indicates that ZNF281 expression is higher in aggressive, undifferentiated stage 4 than in localized stage 1 tumors supporting a central role of ZNF281 in affecting the differentiation of NB. Furthermore, patients with NB with high expression of ZNF281 have a poor clinical outcome compared with low-expressors. These observations suggest that ZNF281 is a controller of neuronal differentiation that should be evaluated as a prognostic marker in NB.

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Transcription factors Krüppel-like factor 4 and paired box 5 regulate the expression of the Grainyhead-like genes

PLoS ONE ◽

10.1371/journal.pone.0257977 ◽

2021 ◽

Vol 16 (9) ◽

pp. e0257977

Author(s):

Grzegorz Kotarba ◽

Agnieszka Taracha-Wisniewska ◽

Michal Miller ◽

Michal Dabrowski ◽

Tomasz Wilanowski

Keyword(s):

Single Nucleotide Polymorphism ◽

Transcription Factors ◽

Mrna Level ◽

Ectopic Expression ◽

Hek293 Cells ◽

Nucleotide Polymorphism ◽

Regulation Of Expression ◽

Single Nucleotide ◽

Family Code

Genes from the Grainyhead-like (GRHL) family code for transcription factors necessary for the development and maintenance of various epithelia. These genes are also very important in the development of many types of cancer. However, little is known about the regulation of expression of GRHL genes. Previously, there were no systematic analyses of the promoters of GRHL genes or transcription factors that bind to these promoters. Here we report that the Krüppel-like factor 4 (KLF4) and the paired box 5 factor (PAX5) bind to the regulatory regions of the GRHL genes and regulate their expression. Ectopic expression of KLF4 or PAX5 alters the expression of GRHL genes. In KLF4-overexpressing HEK293 cells, the expression of GRHL1 and GRHL3 genes was upregulated by 32% and 60%, respectively, whereas the mRNA level of GRHL2 gene was lowered by 28% when compared to the respective controls. The levels of GRHL1 and GRHL3 expression were decreased by 30% or 33% in PAX5-overexpressing HEK293 cells. The presence of minor frequency allele of single nucleotide polymorphism rs115898376 in the promoter of the GRHL1 gene affected the binding of KLF4 to this site. The evidence presented here suggests an important role of KLF4 and PAX5 in the regulation of expression of GRHL1-3 genes.

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Induction of Early B Cell Factor (EBF) and Multiple B Lineage Genes by the Basic Helix-Loop-Helix Transcription Factor E12

Journal of Experimental Medicine ◽

10.1084/jem.188.4.699 ◽

1998 ◽

Vol 188 (4) ◽

pp. 699-713 ◽

Cited By ~ 190

Author(s):

Barbara L. Kee ◽

Cornelis Murre

Keyword(s):

Transcription Factors ◽

B Cell ◽

B Lymphocytes ◽

Ectopic Expression ◽

Helix Loop Helix ◽

Rag 1 ◽

B Lineage ◽

Early B Cell Factor ◽

Mitogen Activation

The transcription factors encoded by the E2A and early B cell factor (EBF) genes are required for the proper development of B lymphocytes. However, the absence of B lineage cells in E2A- and EBF-deficient mice has made it difficult to determine the function or relationship between these proteins. We report the identification of a novel model system in which the role of E2A and EBF in the regulation of multiple B lineage traits can be studied. We found that the conversion of 70Z/3 pre-B lymphocytes to cells with a macrophage-like phenotype is associated with the loss of E2A and EBF. Moreover, we show that ectopic expression of the E2A protein E12 in this macrophage line results in the induction of many B lineage genes, including EBF, IL7Rα, λ5, and Rag-1, and the ability to induce κ light chain in response to mitogen. Activation of EBF may be one of the critical functions of E12 in regulating the B lineage phenotype since expression of EBF alone leads to the activation of a subset of E12-inducible traits. Our data demonstrate that, in the context of this macrophage line, E12 induces expression of EBF and together these transcription factors coordinately regulate numerous B lineage–associated genes.

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The role of combinational coding by homeodomain and bHLH transcription factors in retinal cell fate specification

Developmental Biology ◽

10.1016/j.ydbio.2005.05.041 ◽

2005 ◽

Vol 285 (1) ◽

pp. 101-115 ◽

Cited By ~ 41

Author(s):

J.C.-C. Wang ◽

W.A. Harris

Keyword(s):

Transcription Factors ◽

Cell Fate ◽

Retinal Cell ◽

Cell Fate Specification ◽

Fate Specification ◽

Bhlh Transcription Factors

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MiR-135b Induces Osteosarcoma Invasion by the Modulation of FOXO-1 and c-Myc

International Journal of Cancer Management ◽

10.5812/ijcm.101577 ◽

2020 ◽

Vol 13 (8) ◽

Author(s):

Behnoosh Tahbazlahafi ◽

Malihe Paknejad ◽

Shiva Shahmohamadnejad ◽

Alireza Mirzaei ◽

Khodamorad Jamshidi ◽

...

Keyword(s):

Transcription Factors ◽

Cell Line ◽

Ectopic Expression ◽

Migration And Invasion ◽

Cellular Functions ◽

Tissue Samples ◽

Invasion And Migration ◽

Saos2 Cell ◽

And Migration

Background: Osteosarcoma (OS) is the most common type of bone malignancy. Many studies have attempted to find the association between microRNAs and cancer-associated processes. Alterations in miRNA expression through genetic or epigenetic changes, impairment of transcription factors, and ectopic expression of miRNAs induce the development and progression of cancer. Although miR-135b has been thoroughly documented as an oncogene in the majority of studies, some controversies remain about the conflicting role of miR-135b as a tumor-suppressor. Objectives: The present study aimed at investigating the oncogenic and/or tumor-suppressing role of miR-135b in human OS. Methods: In this study, 21 OS tissue samples, along with 21 adjacent bone tissues (normal) as control specimens were collected to analyze the expression of miR-135b. The Saos2 cell-line was transiently transfected with the miR-135b mimic and inhibitor to assess its effect on two critical transcription factors, namely FOXO-1 and c-Myc. qRT-PCR was performed to quantify the expression of miR-135b in both OS tissues and the Saos2 cell-line. The MTT, cell migration, and cell invasion assays were used to characterize the miR-135b function. The western blot analysis was carried out to monitor the targets of miR-135b. Finally, the changes in cellular functions such as migration and invasion, following the transfection of miR-135b mimic and inhibitor, were verified. Results: The results showed that in comparison with the adjacent normal bone tissues, the expression of miR-135b was higher in OS tissue samples, which inversely correlated with the expression rate of FOXO-1, whereas the expression of c-Myc had a direct relationship to miR-135b expression. Functionally, the miR-135b mimic led to an increase in cell proliferation, invasion, and migration of OS cancer cells. Conclusions: MiR-135b induces the proliferation and invasion of OS cells by the degradation of FOXO-1 and upregulation of c-Myc.

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