scholarly journals Neural Transcription Factors: from Embryos to Neural Stem Cells

2014 ◽  
Vol 37 (10) ◽  
pp. 705-712 ◽  
Author(s):  
Hyun-Kyung Lee ◽  
Hyun-Shik Lee ◽  
Sally A. Moody
Keyword(s):  
Stem Cells ◽  
Transcription Factors ◽  
Neural Stem Cells

scholarly journals Direct Reprogramming of Mouse Fibroblasts to Neural Stem Cells by Small Molecules

2016 ◽  
Vol 2016 ◽  
pp. 1-11 ◽  
Author(s):  
Yan-Chuang Han ◽  
Yoon Lim ◽  
Michael D. Duffieldl ◽  
Hua Li ◽  
Jia Liu ◽  
...  
Keyword(s):  
Stem Cells ◽  
Transcription Factors ◽  
Neural Stem Cells ◽  
Small Molecules ◽  
Clinical Medicine ◽  
Viral Vector ◽  
Expression Patterns ◽  
Tumor Formation ◽  
Patient Specific ◽  
Mouse Fibroblasts

Although it is possible to generate neural stem cells (NSC) from somatic cells by reprogramming technologies with transcription factors, clinical utilization of patient-specific NSC for the treatment of human diseases remains elusive. The risk hurdles are associated with viral transduction vectors induced mutagenesis, tumor formation from undifferentiated stem cells, and transcription factors-induced genomic instability. Here we describe a viral vector-free and more efficient method to induce mouse fibroblasts into NSC using small molecules. The small molecule-induced neural stem (SMINS) cells closely resemble NSC in morphology, gene expression patterns, self-renewal, excitability, and multipotency. Furthermore, the SMINS cells are able to differentiate into astrocytes, functional neurons, and oligodendrocytesin vitroandin vivo. Thus, we have established a novel way to efficiently induce neural stem cells (iNSC) from fibroblasts using only small molecules without altering the genome. Such chemical induction removes the risks associated with current techniques such as the use of viral vectors or the induction of oncogenic factors. This technique may, therefore, enable NSC to be utilized in various applications within clinical medicine.

scholarly journals PPARs Expression in Adult Mouse Neural Stem Cells: Modulation of PPARs during Astroglial Differentiaton of NSC

PPAR Research ◽  
2007 ◽  
Vol 2007 ◽  
pp. 1-10 ◽  
Author(s):  
A. Cimini ◽  
L. Cristiano ◽  
E. Benedetti ◽  
B. D'Angelo ◽  
M. P. Cerù
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Cell Proliferation ◽  
Transcription Factors ◽  
Neural Stem Cells ◽  
Osteoblast Differentiation ◽  
Adult Mouse ◽  
Cell Type ◽  
Cell Proliferation And Differentiation ◽  
Proliferation And Differentiation

PPAR isotypes are involved in the regulation of cell proliferation, death, and differentiation, with different roles and mechanisms depending on the specific isotype and ligand and on the differentiated, undifferentiated, or transformed status of the cell. Differentiation stimuli are integrated by key transcription factors which regulate specific sets of specialized genes to allow proliferative cells to exit the cell cycle and acquire specialized functions. The main differentiation programs known to be controlled by PPARs both during development and in the adult are placental differentiation, adipogenesis, osteoblast differentiation, skin differentiation, and gut differentiation. PPARs may also be involved in the differentiation of macrophages, brain, and breast. However, their functions in this cell type and organs still awaits further elucidation. PPARs may be involved in cell proliferation and differentiation processes of neural stem cells (NSC). To this aim, in this work the expression of the three PPAR isotypes and RXRs in NSC has been investigated.

scholarly journals STEM-25. HDAC1 IS ESSENTIAL FOR GLIOMA STEM CELL SURVIVAL

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi239-vi239
Author(s):  
Costanza Lo Cascio ◽  
James McNamara ◽  
Ernesto Luna Melendez ◽  
Shwetal Mehta
Keyword(s):  
Stem Cells ◽  
Transcription Factors ◽  
Neural Stem Cells ◽  
Malignant Glioma ◽  
Radiation Treatment ◽  
High Grade Glioma ◽  
Dependent Manner ◽  
Minimal Impact ◽  
Histone Deacetylase 1

Abstract OLIG2 is a central nervous system-specific transcription factor that is expressed in almost all diffuse gliomas. It is also one of the key core transcription factors that can reprogram differentiated glioma cells to highly tumorigenic glioma stem-like cells (GSCs). We have previously shown that expression of OLIG2 is critical for glioma growth both in a genetically relevant mouse model as well as in patient-derived xenograft models. Our work suggests that a small molecule inhibitor of OLIG2 could serve as a highly targeted therapy for high-grade glioma; however, transcription factors are generally very difficult to target because their interactions with DNA and co-regulatory proteins involve large and complex surface area contacts. Our laboratory has shown that OLIG2 functions are regulated through interactions with distinct co-regulator proteins in normal neural stem cells. However, there are currently no reports on interactors that promote the proto-oncogenic functions of OLIG2 in malignant glioma. In this study, we employed two independent proteomics screens identify tumor-specific, druggable OLIG2 co-regulators as possible surrogate targets to suppress OLIG2 function in glioma. These screens led to the identification of a novel OLIG2 partner protein: Histone Deacetylase 1 (HDAC1). We confirmed that this interaction occurs in both murine and human glioma models. Although HDACs are ubiquitously expressed and are known to be functionally redundant, we show that ablation of HDAC1 alone significantly decreases the stemness and proliferation capacity of patient-derived GSCs in a p53-dependent manner, while having a minimal impact on normal human neural stem cells and astrocytes. Furthermore, we demonstrate that knockdown of HDAC1, in combination with ionizing radiation treatment, significantly alters the growth pattern of intracranial tumors in vivo. We demonstrate that HDAC1 function is critical for GSC growth and provide a strong rationale for targeting the OLIG2-HDAC1 interaction in malignant glioma.

Sox2 regulatory sequences direct expression of a (beta)-geo transgene to telencephalic neural stem cells and precursors of the mouse embryo, revealing regionalization of gene expression in CNS stem cells

Development ◽  
2000 ◽  
Vol 127 (11) ◽  
pp. 2367-2382 ◽  
Author(s):  
M.V. Zappone ◽  
R. Galli ◽  
R. Catena ◽  
N. Meani ◽  
S. De Biasi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Spinal Cord ◽  
Stem Cells ◽  
Transcription Factors ◽  
Neural Stem Cells ◽  
Ventricular Zone ◽  
Specific Gene ◽  
Regulatory Sequences ◽  
Enhancer Element ◽  
Dorsal Telencephalon

Sox2 is one of the earliest known transcription factors expressed in the developing neural tube. Although it is expressed throughout the early neuroepithelium, we show that its later expression must depend on the activity of more than one regionally restricted enhancer element. Thus, by using transgenic assays and by homologous recombination-mediated deletion, we identify a region upstream of Sox2 (−5.7 to −3.3 kb) which can not only drive expression of a (beta)-geo transgene to the developing dorsal telencephalon, but which is required to do so in the context of the endogenous gene. The critical enhancer can be further delimited to an 800 bp fragment of DNA surrounding a nuclease hypersensitive site within this region, as this is sufficient to confer telencephalic expression to a 3.3 kb fragment including the Sox2 promoter, which is otherwise inactive in the CNS. Expression of the 5.7 kb Sox2(beta)-geo transgene localizes to the neural plate and later to the telencephalic ventricular zone. We show, by in vitro clonogenic assays, that transgene-expressing (and thus G418-resistant) ventricular zone cells include cells displaying functional properties of stem cells, i.e. self-renewal and multipotentiality. We further show that the majority of telencephalic stem cells express the transgene, and this expression is largely maintained over two months in culture (more than 40 cell divisions) in the absence of G418 selective pressure. In contrast, stem cells grown in parallel from the spinal cord never express the transgene, and die in G418. Expression of endogenous telencephalic genes was similarly observed in long-term cultures derived from the dorsal telencephalon, but not in spinal cord-derived cultures. Thus, neural stem cells of the midgestation embryo are endowed with region-specific gene expression (at least with respect to some networks of transcription factors, such as that driving telencephalic expression of the Sox2 transgene), which can be inherited through multiple divisions outside the embryonic environment.

Identification of enhancers that drive the spatially restricted expression of Vsx1 and Rx in the outer proliferation center of the developing Drosophila optic lobe

Genome ◽  
2020 ◽  
pp. 1-9
Author(s):  
Ishrat Maliha Islam ◽  
June Ng ◽  
Priscilla Valentino ◽  
Ted Erclik
Keyword(s):  
Stem Cells ◽  
Transcription Factors ◽  
Neural Stem Cells ◽  
Optic Lobe ◽  
Cell Types ◽  
Temporal Patterning ◽  
Spatial Factors ◽  
Conserved Sequences ◽  
Evolutionarily Conserved ◽  
Powerful Mechanism

Combinatorial spatial and temporal patterning of stem cells is a powerful mechanism for the generation of neural diversity in insect and vertebrate nervous systems. In the developing Drosophila medulla, the neural stem cells of the outer proliferation center (OPC) are spatially patterned by the mutually exclusive expression of three homeobox transcription factors: Vsx1 in the center of the OPC crescent (cOPC), Optix in the main arms (mOPC), and Rx in the posterior tips (pOPC). These spatial factors act together with a temporal cascade of transcription factors in OPC neuroblasts to specify the greater than 80 medulla cell types. Here, we identify the enhancers that are sufficient to drive the spatially restricted expression of the Vsx1 and Rx genes in the OPC. We show that removal of the cOPC enhancer in the Muddled inversion mutant leads to the loss of Vsx1 expression in the cOPC. Analysis of the evolutionarily conserved sequences within these enhancers suggests that direct repression by Optix may restrict the expression of Vsx1 and Rx to the cOPC and pOPC, respectively.

scholarly journals A comprehensive temporal patterning gene network in Drosophila medulla neuroblasts revealed by single-cell RNA sequencing

2021 ◽  
Author(s):  
Hailun Zhu ◽  
Sihai Dave Zhao ◽  
Alokananda Ray ◽  
Yu Zhang ◽  
Xin Li
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Transcription Factors ◽  
Neural Stem Cells ◽  
Single Cell ◽  
Rna Sequencing ◽  
Gene Network ◽  
Temporal Patterning ◽  
Single Cell Rna Sequencing ◽  
High Gradients

During development, neural stem cells are temporally patterned to sequentially generate a variety of neural types before exiting the cell cycle. Temporal patterning is well-studied in Drosophila, where neural stem cells called neuroblasts sequentially express cascades of Temporal Transcription Factors (TTFs) to control the birth-order dependent neural specification. However, currently known TTFs were mostly identified through candidate approaches and may not be complete. In addition, many fundamental questions remain concerning the TTF cascade initiation, progression, and termination. It is also not known why temporal progression only happens in neuroblasts but not in their differentiated progeny. In this work, we performed single-cell RNA sequencing of Drosophila medulla neuroblasts of all ages to study the temporal patterning process with single-cell resolution. Our scRNA-seq data revealed that sets of genes involved in different biological processes show high to low or low to high gradients as neuroblasts age. We also identified a list of novel TTFs, and experimentally characterized their roles in the temporal progression and neural fate specification. Our study revealed a comprehensive temporal gene network that patterns medulla neuroblasts from start to end. Furthermore, we found that the progression and termination of this temporal cascade also require transcription factors differentially expressed along the differentiation axis (neuroblasts -> -> neurons). Lola proteins function as a speed modulator of temporal progression in neuroblasts; while Nerfin-1, a factor required to suppress de-differentiation in post-mitotic neurons, acts at the final temporal stage together with the last TTF of the cascade, to promote the switch to gliogenesis and the cell cycle exit. Our comprehensive study of the medulla neuroblast temporal cascade illustrated mechanisms that might be conserved in the temporal patterning of neural stem cells.

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