Identification of Both General and Region-Specific Embryonic CNS Enhancer Elements in the Nestin Promoter

Lothian, Carina; Prakash, Nilima; Lendahl, Urban; Wahlström, Gunilla

doi:10.1006/excr.1999.4417

Cited by 70 publications

(66 citation statements)

References 54 publications

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“…Moreover, it has also been reported that several recombinant nuclear hormone receptors (i.e. thyroid hormone receptors, retinoid X receptor, retinoic acid receptor, and chicken ovalbumin upstream promoter-transcription factor) were able to bind in vitro to the HRE/CRE-like sequence (41). Nuclear extracts prepared from a TTF-1-expressing 3T3 clone were able to specifically bind in EMSA to the footprinted region on the nestin 257-bp-long enhancer encompassing the HRE/CRE-like sequences.…”

Section: Discussionmentioning

confidence: 99%

Nestin Is a Neuroepithelial Target Gene of Thyroid Transcription Factor-1, a Homeoprotein Required for Forebrain Organogenesis

Lonigro

Donnini

Zappia

et al. 2001

Journal of Biological Chemistry

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Thyroid transcription factor-1 (TTF-1, also known as NKX2.1 and T/EBP), a transcription factor belonging to the NKX-2 family of homeodomain-containing genes, plays an essential role in the organogenesis of the thyroid gland, lung, and ventral forebrain. Nestin is an intermediate filament protein strongly expressed in multipotential neuroepithelial stem cells and rapidly down-regulated during postnatal life. Here we show that stable fibroblastic clones expressing TTF-1 acquire a phenotype reminiscent of neuroepithelial cells in culture and up-regulate the endogenous nestin gene. TTF-1 transactivates in HeLa and NIH3T3 cells a reporter gene driven by a central nervous system-specific enhancer element from the second intron of the rat nestin gene, where it recognizes a DNA-binding site (NestBS) whose sequence resembles a nuclear hormone/cAMP-responsive element very different from canonical TTF-1 binding sites. Nuclear extracts from the head of mouse embryos form a retarded complex with NestBS of the same mobility of the extracts obtained from TTF1-expressing clones, which is either abolished or supershifted in the presence of two different antibodies recognizing the TTF-1 protein. Thus, the neuroepithelial marker nestin is a direct central nervous system-specific target gene of TTF-1, leading to the hypothesis that it might be the effector through which TTF-1 plays its role in the organogenesis of the forebrain.Thyroid transcription factor-1 (TTF-1), 1 also known as NKX2.1 and T/EBP, is a member of the NKX family of homeodomain-containing genes related to NK Drosophila genes (1). TTF-1 plays a fundamental role in the tissue-specific expression of several thyroid-specific (i.e. thyroglobulin, thyroperoxidase, thyrotropin receptor, and sodium iodide symporter) and lung-specific (i.e. surfactant proteins and the Clara cell secretory protein) genes (2-7). TTF-1 has been reported to be expressed also in the adult rat parathyroid cells and several other adult tissues (including skin, esophagus, retina, anterior pituitary, cerebellum, and hippocampus) (8,9). Recently, it has been shown that postnatal hypothalamic TTF-1 expression is strongly and transiently up-regulated immediately before puberty in female rats and is associated with the neuroendocrine process of female sexual development (10).TTF-1 is expressed at the onset of thyroid and lung organogenesis, and in restricted areas of the developing forebrain, namely within the diencephalon (i.e. in the hypothalamus and neurohypophysis) and the telencephalon (i.e. in the medial ganglionic eminence) (11). The crucial role exerted by TTF-1 in thyroid, lung, and ventral forebrain organogenesis has been directly demonstrated by the analysis of the phenotype of TTF-1 Ϫ/Ϫ mice. In fact, homozygous mutant mice were born dead and lacked completely the thyroid gland, lung parenchyma, and the entire pituitary, and extensive defects were found in the ventral region of the forebrain (12). In addition, it has been reported that, in TTF-1 knockout mice, a ventral-to-dorsal transformat...

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Section: Discussionmentioning

confidence: 99%

Nestin Is a Neuroepithelial Target Gene of Thyroid Transcription Factor-1, a Homeoprotein Required for Forebrain Organogenesis

Lonigro

Donnini

Zappia

et al. 2001

Journal of Biological Chemistry

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“…A recent study identified two genes, Lmx1a (LIM homeobox transcription factor 1, alpha) and Msx1 (msh homeobox homolog 1), as major upstream regulators of the dopaminergic neuronal subtype specification. Expression of Lmx1a driven by the neural-specific nestin enhancer coupled to a minimal thymidine kinase promoter (Lothian et al, 1999) induced the maturation of mouse embryonic stem cells (ESCs) into ventral midbrain dopaminergic neurons when sonic hedgehog (SHH) and fibroblast growth factor 8 (FGF8) were present in the medium (Andersson et al, 2006b).…”

Section: Introductionmentioning

confidence: 99%

Effects on Differentiation of Embryonic Ventral Midbrain Progenitors by Lmx1a, Msx1, Ngn2, and Pitx3

Roybon¹,

Hjalt²,

Christophersen³

et al. 2008

J. Neurosci.

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Neurons derived from neural stem cells could potentially be used for cell therapy in neurodegenerative disorders, such as Parkinson's disease. To achieve controlled differentiation of neural stem cells, we expressed transcription factors involved in the development of midbrain dopaminergic neurons in rat and human neural progenitors. Using retroviral-mediated transgene delivery, we overexpressed Lmx1a (LIM homeobox transcription factor 1, alpha), Msx1 (msh homeobox homolog 1), Ngn2 (neurogenin 2), or Pitx3 (paired-like homeodomain transcription factor 3) in neurospheres derived from embryonic day 14.5 rat ventral mesencephalic progenitors. We also expressed either Lmx1a or Msx1 in the human embryonic midbrain-derived progenitor cell line NGC-407. Rat cells transduced with Ngn2 exited the cell cycle and expressed the neuronal marker microtubule-associated protein 2 and catecholamine-neuron protein vesicular monoamine transporter 2. Interestingly, Pitx3 downregulated the expression of SOX2 (SRY-box containing gene 2) and Nestin, altered cell morphology, but never induced neuronal or glial differentiation. Ngn2 exhibited a strong neuron-inducing effect. In contrast, few Lmx1a-transduced cells matured into neurons, and Msx1 overexpression promoted oligodendrogenesis rather than neuronal differentiation. Importantly, none of these four genes, alone or in combination, enhanced differentiation of rat neural stem cells into dopaminergic neurons. Notably, the overexpression of Lmx1a, but not Msx1, in human neural progenitors increased the yield of tyrosine hydroxylase-immunoreactive cells by threefold. Together, we demonstrate that induced overexpression of transcription factor genes has profound and specific effects on the differentiation of rat and human midbrain progenitors, although few dopamine neurons are generated.

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“…For example, Nestin and Vimentin are expressed in the early phase of CNS development and are later replaced by neurofilaments and GFAP in neurons and astrocytes respectively. In consistence with this genetic reprogramming, GSCs, like NSCs, express Nestin but not GFAP, and differentiated GBM cells do not express Nestin but GFAP [4,12,18,38,52].…”

Section: Discussionmentioning

confidence: 98%

“…A 714 bp NSC-specific Nestin enhancer (located in the second intron of the human Nestin gene) [18,38,39] was PCR-amplified using a template of genomic DNA isolated from U87 cells. The amplified Nestin enhancer fragment was cloned into the Bgl II restriction site of TP222 vector in which the luciferase gene was driven by an 81 bp minimal thymidine kinase (TK) promoter [40].…”

Section: Luciferase Reporter Constructs and Luciferase Assaymentioning

confidence: 99%

“…To determine the transcriptional activity of GFAP and Nestin in U251 and U87 cells, we used luciferase reporter constructs driven by either a 2.2 kb human GFAP promoter [36,37] or a 714 bp NSC-specific Nestin enhancer (located in the second intron of the human Nestin gene) [18,38,39] linked to a minimal thymidine kinase (TK) promoter [40] (Fig. 1E).…”

Section: Tumorigenic Potential Of Gbm Cells Correlates With Gfap and mentioning

confidence: 99%

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p300- and Myc-mediated regulation of glioblastoma multiforme cell differentiation

et al. 2010

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AbsTRACT:Tumorigenic potential of glioblastoma multiforme (GBM) cells is, in part, attributable to their undifferentiated (neural stem cell-like) phenotype. Astrocytic differentiation of GBM cells is associated with transcriptional induction of Glial Fibrillary Acidic Protein (GFAP) and repression of Nestin, whereas the reciprocal transcription program operates in undifferentiated GBM cells. The molecular mechanisms underlying the regulation of these transcription programs remain elusive. Here, we show that the transcriptional co-activator p300 was expressed in GBM tumors and cell lines and acted as an activator of the GFAP gene and a repressor of the Nestin gene. On the other hand, Myc (formerly known as c-Myc overrode these p300 functions by repressing the GFAP gene and inducing the Nestin gene in GBM cells. Moreover, RNAi-mediated inhibition of p300 expression significantly enhanced the invasion potential of GBM cells in vitro. Taken together, these data suggest that dedifferentiated/undifferentiated GBM cells are more invasive than differentiated GBM cells. Because invasion is a major cause of GBM morbidity, differentiation therapy may improve the clinical outcome.

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Identification of Both General and Region-Specific Embryonic CNS Enhancer Elements in the Nestin Promoter

Cited by 70 publications

References 54 publications

Nestin Is a Neuroepithelial Target Gene of Thyroid Transcription Factor-1, a Homeoprotein Required for Forebrain Organogenesis

Nestin Is a Neuroepithelial Target Gene of Thyroid Transcription Factor-1, a Homeoprotein Required for Forebrain Organogenesis

Effects on Differentiation of Embryonic Ventral Midbrain Progenitors by Lmx1a, Msx1, Ngn2, and Pitx3

p300- and Myc-mediated regulation of glioblastoma multiforme cell differentiation

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