Disrupted development of the cerebral hemispheres in transgenic mice expressing the mammalian Groucho homologue Transducin-like-Enhancer of split 1 in postmitotic neurons

Yao, Jing; Liu, Yanling; Lo, Rita; Tretjakoff, Irene; Peterson, Alan C.; Stifani, Stefano

doi:10.1016/s0925-4773(00)00278-1

Cited by 51 publications

(63 citation statements)

References 47 publications

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“…Tissue was mechanically triturated and incubated for 15 min on ice, followed by centrifugation at 14 000 Â g for 15 min. The supernatant was recovered and subjected to immunoprecipitation of endogenous Gro/TLE1 using rabbit anti-Gro/TLE1 10,12,23 or control rabbit serum using protein A/G-Plus agarose beads (Santa Cruz Biotechnology, Santa Cruz, CA, USA). Collected and thoroughly rinsed immunoprecipitates were resuspended in 60 mM Tris/HCl, pH 6.8, 10% glycerol and 2% SDS, followed by incubation at room temperature for 10 min and recovery of the eluted material by quick centrifugation.…”

Section: Discussionmentioning

confidence: 99%

“…[3][4][5] In both invertebrate and vertebrate species, Notch-induced Hes proteins, such as Hes1, repress transcription together with the general transcriptional corepressors of the Groucho/transducin-like Enhancer of split (Gro/TLE) family. [6][7][8] Gro/TLE1 is expressed in undifferentiated cortical neural progenitor cells in which Hes1 is also expressed [9][10][11] and inhibits cortical neuronal differentiation in vivo and in vitro. [10][11][12] Moreover, Hes1 and Gro/TLE1 physically interact, repress transcription together and localize to common promoter regions in vivo.…”

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confidence: 99%

“…[6][7][8] Gro/TLE1 is expressed in undifferentiated cortical neural progenitor cells in which Hes1 is also expressed [9][10][11] and inhibits cortical neuronal differentiation in vivo and in vitro. [10][11][12] Moreover, Hes1 and Gro/TLE1 physically interact, repress transcription together and localize to common promoter regions in vivo. [13][14][15] Hes1 and Gro/TLE1 are expressed in neural progenitor cells during both the proliferative and differentiative phases of cortical neurogenesis, suggesting the existence of mechanisms that either promote or inhibit their anti-neurogenic function at different stages of cortical neuronal differentiation.…”

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Prolyl isomerase Pin1 and protein kinase HIPK2 cooperate to promote cortical neurogenesis by suppressing Groucho/TLE:Hes1-mediated inhibition of neuronal differentiation

et al. 2013

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The Groucho/transducin-like Enhancer of split 1 (Gro/TLE1):Hes1 transcriptional repression complex acts in cerebral cortical neural progenitor cells to inhibit neuronal differentiation. The molecular mechanisms that regulate the anti-neurogenic function of the Gro/TLE1:Hes1 complex during cortical neurogenesis remain to be defined. Here we show that prolyl isomerase Pin1 (peptidyl-prolyl cis-trans isomerase NIMA-interacting 1) and homeodomain-interacting protein kinase 2 (HIPK2) are expressed in cortical neural progenitor cells and form a complex that interacts with the Gro/TLE1:Hes1 complex. This association depends on the enzymatic activities of both HIPK2 and Pin1, as well as on the association of Gro/TLE1 with Hes1, but is independent of the previously described Hes1-activated phosphorylation of Gro/TLE1. Interaction with the Pin1:HIPK2 complex results in Gro/TLE1 hyperphosphorylation and weakens both the transcriptional repression activity and the anti-neurogenic function of the Gro/ TLE1:Hes1 complex. These results provide evidence that HIPK2 and Pin1 work together to promote cortical neurogenesis, at least in part, by suppressing Gro/TLE1:Hes1-mediated inhibition of neuronal differentiation. Cell Death and Differentiation (2014) 21, 321-332; doi:10.1038/cdd.2013.160; published online 22 November 2013During mammalian brain development, the ventricular zone of the dorsolateral region of the alar telencephalon (neocortex) contains undifferentiated neural progenitor cells that initially undergo symmetric (proliferative) divisions to generate two new progenitor cells and later undergo asymmetric (differentiative) divisions to give rise to a new mitotic progenitor and a post-mitotic neuron.

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Section: Discussionmentioning

confidence: 99%

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Prolyl isomerase Pin1 and protein kinase HIPK2 cooperate to promote cortical neurogenesis by suppressing Groucho/TLE:Hes1-mediated inhibition of neuronal differentiation

et al. 2013

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“…TLE1, the most studied among the Groucho family proteins in mammalian systems, is widely expressed in different tissues and cell types and has been implicated in neuronal differentiation (3,4) and pancreatic beta cell development (5). TLE1 has tumor suppressor activity (6)(7)(8) as well as oncogenic functions in cancer (9,10).…”

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Tle1 tumor suppressor negatively regulates inflammation in vivo and modulates NF-κB inflammatory pathway

Ramasamy

Sáez

Mukhopadhyay

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Tle1 (transducin-like enhancer of split 1) is a corepressor that interacts with a variety of DNA-binding transcription factors and has been implicated in many cellular functions; however, physiological studies are limited. Tle1-deficient (Tle1 Δ/Δ ) mice, although grossly normal at birth, exhibit skin defects, lung hypoplasia, severe runting, poor body condition, and early mortality. Tle1 Δ/Δ mice display a chronic inflammatory phenotype with increased expression of inflammatory cytokines and chemokines in the skin, lung, and intestine and increased circulatory IL-6 and G-CSF, along with a hematopoietic shift toward granulocyte macrophage progenitor and myeloid cells. Tle1 Δ/Δ macrophages produce increased inflammatory cytokines in response to Toll-like receptor (TLR) agonists and lipopolysaccharides (LPS), and Tle1 Δ/Δ mice display an enhanced inflammatory response to ear skin 12-O-tetradecanoylphorbol-13-acetate treatment. Loss of Tle1 not only results in increased phosphorylation and activation of proinflammatory NF-κB but also results in decreased Hes1 (hairy and enhancer of split-1), a negative regulator of inflammation in macrophages. Furthermore, Tle1 Δ/Δ mice exhibit accelerated growth of B6-F10 melanoma xenografts. Our work provides the first in vivo evidence, to our knowledge, that TLE1 is a major counterregulator of inflammation with potential roles in a variety of inflammatory diseases and in cancer progression.T ransducin-like enhancer of split 1 (TLE1) belongs to a family of corepressor proteins called transducin-like enhancer of split, or TLEs. Groucho, the TLE homolog in Drosophila, has crucial roles in neurogenesis, segmentation, and sex determination (1). These corepressors do not bind directly to DNA but rather interact with many different classes of transcription factors and help create a repressor complex (1, 2).Vertebrates express five different TLEs (TLE1-4, AES), although the distinct functions of each of the TLEs has not been well determined. TLE1, the most studied among the Groucho family proteins in mammalian systems, is widely expressed in different tissues and cell types and has been implicated in neuronal differentiation (3, 4) and pancreatic beta cell development (5). TLE1 has tumor suppressor activity (6-8) as well as oncogenic functions in cancer (9, 10). TLE1 associates with many important transcription factors integral for cell proliferation and differentiation, including Runx2 to block rRNA expression (11), HES1 to suppresses MASH2 expression (12), and TCF/LEF proteins to block Wnt target gene activation (13). TLE1 also represses NF-κB activity (14,15). Involvement in these diverse cellular functions and diseases was studied primarily in vitro or using in vivo overexpression systems. The major physiological function of TLE1, however, remains poorly understood.A few recent studies suggest TLE1 might regulate immune function. For example, a single noncoding nucleotide polymorphism within the TLE1 locus was associated with inflammatory bowel diseases (16), and in human monocytes,...

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“…41 In brain development, Gro/ TLE proteins expressed in proliferating neural progenitor cells have been found to be involved in neurogenesis through the maintenance of the undifferentiated state by inhibiting or delaying neuronal differentiation. 43,44 A missense mutation in the conserved leucine residue to proline (c.98T4C/p. (L33P)) in the octapeptide domain of ARX has been identified in a family affected with non-syndromic ID.…”

Section: Discussionmentioning

confidence: 99%

Reinitiation of mRNA translation in a patient with X-linked infantile spasms with a protein-truncating variant in ARX

et al. 2015

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Mutations in the Aristaless-related homeobox gene (ARX) lead to a range of X-linked intellectual disability phenotypes, with truncating variants generally resulting in severe X-linked lissencephaly with ambiguous genitalia (XLAG), and polyalanine expansions and missense variants resulting in infantile spasms. We report two male patients with early-onset infantile spasms in whom a novel c.34G4T (p.(E12*)) variant was identified in the ARX gene. A similar variant c.81C4G (p.(Y27*)), has previously been described in two affected cousins with early-onset infantile spasms, leading to reinitiation of ARX mRNA translation resulting in an N-terminal truncated protein. We show that the novel c.34G4T (p.(E12*)) variant also reinitiated mRNA translation at the next AUG codon (c.121-123 (p.M41)), producing the same N-terminally truncated protein. The production of both of these truncated proteins was demonstrated to be at markedly reduced levels using in vitro cell assays. Using luciferase reporter assays, we demonstrate that transcriptional repression capacity of ARX was diminished by both the loss of the N-terminal corepressor octapeptide domain, as a consequence of truncation, and the marked reduction in mutant protein expression. Our study indicates that premature termination mutations very early in ARX lead to reinitiation of translation to produce N-terminally truncated protein at markedly reduced levels of expression. We conclude that even low levels of N-terminally truncated ARX is sufficient to improve the patient's phenotype compared with the severe phenotype of XLAG that includes malformations of the brain and genitalia normally seen in complete loss-of-function mutations in ARX.

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Disrupted development of the cerebral hemispheres in transgenic mice expressing the mammalian Groucho homologue Transducin-like-Enhancer of split 1 in postmitotic neurons

Cited by 51 publications

References 47 publications

Prolyl isomerase Pin1 and protein kinase HIPK2 cooperate to promote cortical neurogenesis by suppressing Groucho/TLE:Hes1-mediated inhibition of neuronal differentiation

Prolyl isomerase Pin1 and protein kinase HIPK2 cooperate to promote cortical neurogenesis by suppressing Groucho/TLE:Hes1-mediated inhibition of neuronal differentiation

Tle1 tumor suppressor negatively regulates inflammation in vivo and modulates NF-κB inflammatory pathway

Reinitiation of mRNA translation in a patient with X-linked infantile spasms with a protein-truncating variant in ARX

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