Gene Symbol: Tle4
Description: transducin-like enhancer of split 4
Alias: 5730411M05Rik, AA792082, Bce-1, Bce1, ESTM13, ESTM14, Grg4, X83332, X83333, grg-4, transducin-like enhancer protein 4, B lymphocyte gene 1, groucho-related protein 4, transducin-like enhancer of split 4, homolog of Drosophila E(spl)
Species: mouse
Products:     Tle4

Top Publications

  1. Dehni G, Liu Y, Husain J, Stifani S. TLE expression correlates with mouse embryonic segmentation, neurogenesis, and epithelial determination. Mech Dev. 1995;53:369-81 pubmed
  2. Brantjes H, Roose J, van de Wetering M, Clevers H. All Tcf HMG box transcription factors interact with Groucho-related co-repressors. Nucleic Acids Res. 2001;29:1410-9 pubmed
    ..Although Grg-5 contains the GP homology domain that mediates HDAC binding in long Grg proteins, Grg-5 fails to bind this co-repressor, explaining how it can de-repress transcription. ..
  3. Yao J, Liu Y, Lo R, Tretjakoff I, Peterson A, Stifani S. Disrupted development of the cerebral hemispheres in transgenic mice expressing the mammalian Groucho homologue transducin-like-enhancer of split 1 in postmitotic neurons. Mech Dev. 2000;93:105-15 pubmed
    ..These results provide the first direct evidence that TLE1 is an important negative regulator of postmitotic neuronal differentiation in the mammalian central nervous system. ..
  4. Yao J, Liu Y, Husain J, Lo R, Palaparti A, Henderson J, et al. Combinatorial expression patterns of individual TLE proteins during cell determination and differentiation suggest non-redundant functions for mammalian homologs of Drosophila Groucho. Dev Growth Differ. 1998;40:133-46 pubmed
    ..TLE1 is up-regulated and TLE2 and TLE4 are down-regulated to different extents during early stages of differentiation...
  5. Koop K, Macdonald L, Lobe C. Transcripts of Grg4, a murine groucho-related gene, are detected in adjacent tissues to other murine neurogenic gene homologues during embryonic development. Mech Dev. 1996;59:73-87 pubmed
    ..We have isolated murine Grg4 cDNAs and examined Grg4 expression during embryogenesis...
  6. Eberhard D, Jimenez G, Heavey B, Busslinger M. Transcriptional repression by Pax5 (BSAP) through interaction with corepressors of the Groucho family. EMBO J. 2000;19:2292-303 pubmed
    ..In a yeast two-hybrid screen, the groucho-related gene product Grg4 was identified as a Pax5 partner protein...
  7. Kivimäe S, Martin P, Kapfhamer D, Ruan Y, Heberlein U, Rubenstein J, et al. Abnormal behavior in mice mutant for the Disc1 binding partner, Dixdc1. Transl Psychiatry. 2011;1:e43 pubmed publisher
    ..Our results suggest that Dixdc1(-/-) mice will be a useful tool to elucidate molecular pathophysiology involving Disc1 in major mental illnesses. ..
  8. Nakayama H, Liu Y, Stifani S, Cross J. Developmental restriction of Mash-2 expression in trophoblast correlates with potential activation of the notch-2 pathway. Dev Genet. 1997;21:21-30 pubmed
    ..These data suggest that Notch signaling through activation of HES transcriptional repressors may play a role in murine placental development. ..
  9. Sharma M, Fopma A, Brantley J, Vanden Heuvel G. Coexpression of Cux-1 and Notch signaling pathway components during kidney development. Dev Dyn. 2004;231:828-38 pubmed
    ..Taken together, these results suggest that Cux-1 may function in the context of the Notch signaling pathway in multiple tissues during mammalian embryogenesis...

More Information


  1. Petersen P, Zou K, Krauss S, Zhong W. Continuing role for mouse Numb and Numbl in maintaining progenitor cells during cortical neurogenesis. Nat Neurosci. 2004;7:803-11 pubmed
  2. Shen Q, Wang Y, Dimos J, Fasano C, Phoenix T, Lemischka I, et al. The timing of cortical neurogenesis is encoded within lineages of individual progenitor cells. Nat Neurosci. 2006;9:743-51 pubmed
    ..Our data demonstrate that neural stem cells change neuropotency during development and have a window of plasticity when restrictions can be reversed. ..
  3. Rave Harel N, Miller N, Givens M, Mellon P. The Groucho-related gene family regulates the gonadotropin-releasing hormone gene through interaction with the homeodomain proteins MSX1 and OCT1. J Biol Chem. 2005;280:30975-83 pubmed
    ..Taken together, these data suggest that the dynamic switch between activation and repression of GnRH transcription is mediated by recruitment of the GRG co-regulators. ..
  4. Leon C, Lobe C. Grg3, a murine Groucho-related gene, is expressed in the developing nervous system and in mesenchyme-induced epithelial structures. Dev Dyn. 1997;208:11-24 pubmed
    ..Grg3 expression was also consistently detected in epithelial structures undergoing mesenchyme induction. ..
  5. Mortensen A, Schade V, Lamonerie T, Camper S. Deletion of OTX2 in neural ectoderm delays anterior pituitary development. Hum Mol Genet. 2015;24:939-53 pubmed publisher
    ..Otx2 expression early in head development is important for establishing normal craniofacial features including development of the brain, eyes and pituitary gland. ..
  6. Ramos Mejia V, Escalante Alcalde D, Kunath T, Ramírez L, Gertsenstein M, Nagy A, et al. Phenotypic analyses of mouse embryos with ubiquitous expression of Oct4: effects on mid-hindbrain patterning and gene expression. Dev Dyn. 2005;232:180-90 pubmed
    ..Our observations support the hypothesis that Oct4, like zebrafish Pou2, has a conserved function during early brain patterning in mouse. ..
  7. Nielsen J, Thomassen M, Møllgård K, Noraberg J, Jensen N. Zbtb20 defines a hippocampal neuronal identity through direct repression of genes that control projection neuron development in the isocortex. Cereb Cortex. 2014;24:1216-29 pubmed publisher
    ..specification in the developing isocortex, including Cux1, Cux2, Fezf2, Foxp2, Mef2c, Rorb, Satb2, Sox5, Tbr1, Tle4, and Zfpm2...
  8. Wheat J, Krause D, Shin T, Chen X, Wang J, Ding D, et al. The corepressor Tle4 is a novel regulator of murine hematopoiesis and bone development. PLoS ONE. 2014;9:e105557 pubmed publisher
    ..b>Tle4, a transcriptional corepressor, acts as a tumor suppressor gene in a subset of acute myeloid leukemia, yet little ..
  9. Lai H, Klisch T, Roberts R, Zoghbi H, Johnson J. In vivo neuronal subtype-specific targets of Atoh1 (Math1) in dorsal spinal cord. J Neurosci. 2011;31:10859-71 pubmed publisher
    ..Our work establishes on a molecular level that neuronal differentiation bHLH transcription factors have distinct lineage-specific targets. ..
  10. Sessa A, Ciabatti E, Drechsel D, Massimino L, Colasante G, Giannelli S, et al. The Tbr2 Molecular Network Controls Cortical Neuronal Differentiation Through Complementary Genetic and Epigenetic Pathways. Cereb Cortex. 2017;27:3378-3396 pubmed publisher
    ..These data identify TBR2 as a major determinant of the INP-specific traits by regulating both genetic and epigenetic pathways. ..
  11. Urbán N, Martín Ibáñez R, Herranz C, Esgleas M, Crespo E, Pardo M, et al. Nolz1 promotes striatal neurogenesis through the regulation of retinoic acid signaling. Neural Dev. 2010;5:21 pubmed publisher
    ..Nolz1 promotes RA signaling in the LGE, contributing to the striatal neurogenesis during development. ..
  12. Cappello S, Böhringer C, Bergami M, Conzelmann K, Ghanem A, Tomassy G, et al. A radial glia-specific role of RhoA in double cortex formation. Neuron. 2012;73:911-24 pubmed publisher
    ..These data not only demonstrate that RhoA is largely dispensable for migration in neurons but also showed that defects in radial glial cells, rather than neurons, can be sufficient to produce SBH. ..
  13. Bandyopadhyay S, Valdor R, Macian F. Tle4 regulates epigenetic silencing of gamma interferon expression during effector T helper cell tolerance. Mol Cell Biol. 2014;34:233-45 pubmed publisher
    ..In those T cells, calcium signaling triggers the expression of Tle4, a member of the Groucho family of corepressors, which is then recruited to a distal regulatory element in the Ifng ..
  14. Louvi A, Nishimura S, Gunel M. Ccm3, a gene associated with cerebral cavernous malformations, is required for neuronal migration. Development. 2014;141:1404-15 pubmed publisher
    ..Thus, we identify a novel cytoplasmic regulator of neuronal migration and demonstrate that its inactivation in radial glia progenitors and nascent neurons produces severe malformations of cortical development. ..
  15. Allen T, Lobe C. A comparison of Notch, Hes and Grg expression during murine embryonic and post-natal development. Cell Mol Biol (Noisy-le-grand). 1999;45:687-708 pubmed
    ..Our data suggest that the coordinated transcriptional control of these genes occurs during development and that precise Hes and Grg pairings may play a role in mediating the morphogenesis of CNS and epithelialized structures. ..
  16. Slorach E, Chou J, Werb Z. Zeppo1 is a novel metastasis promoter that represses E-cadherin expression and regulates p120-catenin isoform expression and localization. Genes Dev. 2011;25:471-84 pubmed publisher
    ..These results indicate that Zeppo1 is a key regulator of breast cancer progression. ..
  17. Lai T, Jabaudon D, Molyneaux B, Azim E, Arlotta P, Menezes J, et al. SOX5 controls the sequential generation of distinct corticofugal neuron subtypes. Neuron. 2008;57:232-47 pubmed publisher
    ..These data indicate that SOX5 controls the timing of critical fate decisions during corticofugal neuron production and thus subtype-specific differentiation and neocortical neuron diversity. ..
  18. Zhou C, Borello U, Rubenstein J, Pleasure S. Neuronal production and precursor proliferation defects in the neocortex of mice with loss of function in the canonical Wnt signaling pathway. Neuroscience. 2006;142:1119-31 pubmed
    ..This analysis demonstrates that canonical Wnt signaling is required for a diverse array of developmental processes in the neocortex in addition to the previously known roles in regulating precursor proliferation and patterning. ..
  19. Doyle M, Loomis Z, Sussel L. Nkx2.2-repressor activity is sufficient to specify alpha-cells and a small number of beta-cells in the pancreatic islet. Development. 2007;134:515-23 pubmed
    ..a repressor in the islet, we assessed the pancreatic expression of the Groucho co-repressors, Grg1, Grg2, Grg3 and Grg4 (Tle1-Tle4), which have been shown to interact with and modulate Nkx2.2 function...
  20. Rashid M, Belmont J, Carpenter D, Turner C, Olson E. Neural-specific deletion of the focal adhesion adaptor protein paxillin slows migration speed and delays cortical layer formation. Development. 2017;144:4002-4014 pubmed publisher
  21. Muhr J, Andersson E, Persson M, Jessell T, Ericson J. Groucho-mediated transcriptional repression establishes progenitor cell pattern and neuronal fate in the ventral neural tube. Cell. 2001;104:861-73 pubmed
    ..These results imply that the pattern of neurogenesis in the neural tube is achieved through the spatially controlled repression of transcriptional repressors-a derepression strategy of neuronal fate specification. ..
  22. Sessa A, Mao C, Hadjantonakis A, Klein W, Broccoli V. Tbr2 directs conversion of radial glia into basal precursors and guides neuronal amplification by indirect neurogenesis in the developing neocortex. Neuron. 2008;60:56-69 pubmed publisher
    ..Together, these findings identify Tbr2 as a critical factor for the specification of IPCs during corticogenesis. ..
  23. Kwan K, Lam M, Krsnik Z, Kawasawa Y, Lefebvre V, Sestan N. SOX5 postmitotically regulates migration, postmigratory differentiation, and projections of subplate and deep-layer neocortical neurons. Proc Natl Acad Sci U S A. 2008;105:16021-6 pubmed publisher
    ..Thus, SOX5 postmitotically regulates the migration, postmigratory differentiation, and subcortical projections of subplate and deep-layer neurons. ..
  24. Caubit X, Gubellini P, Andrieux J, Roubertoux P, Metwaly M, Jacq B, et al. TSHZ3 deletion causes an autism syndrome and defects in cortical projection neurons. Nat Genet. 2016;48:1359-1369 pubmed publisher
    ..These findings highlight essential roles for Tshz3 in CPN development and function, whose alterations can account for ASD in the newly defined TSHZ3 deletion syndrome. ..
  25. Deboer E, Azevedo R, Vega T, Brodkin J, Akamatsu W, Okano H, et al. Prenatal deletion of the RNA-binding protein HuD disrupts postnatal cortical circuit maturation and behavior. J Neurosci. 2014;34:3674-86 pubmed publisher
    ..Our findings suggest that HuD is necessary for the establishment of neocortical and hippocampal circuitry and is critical for their function. ..
  26. Lang D, Lu M, Huang L, Engleka K, Zhang M, Chu E, et al. Pax3 functions at a nodal point in melanocyte stem cell differentiation. Nature. 2005;433:884-7 pubmed
    ..Thus, a stem cell transcription factor can both determine cell fate and simultaneously maintain an undifferentiated state, leaving a cell poised to differentiate in response to external stimuli. ..
  27. Brinkmeier M, Potok M, Cha K, Gridley T, Stifani S, Meeldijk J, et al. TCF and Groucho-related genes influence pituitary growth and development. Mol Endocrinol. 2003;17:2152-61 pubmed
    ..Thus, we demonstrate that Tcf4 and Aes influence pituitary growth and development, and place Tcf4 and Tle3 in the genetic hierarchy with Prop1. ..
  28. Zhu C, Dyer M, Uchikawa M, Kondoh H, Lagutin O, Oliver G. Six3-mediated auto repression and eye development requires its interaction with members of the Groucho-related family of co-repressors. Development. 2002;129:2835-49 pubmed
    ..Here, we report that Grg4 and Grg5, mouse counterparts of the Drosophila transcriptional co-repressor Groucho, interact with mouse Six3 and ..
  29. Molyneaux B, Goff L, Brettler A, Chen H, Hrvatin S, Rinn J, et al. DeCoN: genome-wide analysis of in vivo transcriptional dynamics during pyramidal neuron fate selection in neocortex. Neuron. 2015;85:275-288 pubmed publisher
    ..This multifaceted study generates a powerful resource and informs understanding of the transcriptional regulation underlying pyramidal neuron diversity in the neocortex. ..
  30. Yang G, Smibert C, Kaplan D, Miller F. An eIF4E1/4E-T complex determines the genesis of neurons from precursors by translationally repressing a proneurogenic transcription program. Neuron. 2014;84:723-39 pubmed publisher
    ..Thus, neural precursors are transcriptionally primed to generate neurons, but an eIF4E/4E-T complex sequesters and represses translation of proneurogenic proteins to determine appropriate neurogenesis. ..
  31. Heimbucher T, Murko C, Bajoghli B, Aghaallaei N, Huber A, Stebegg R, et al. Gbx2 and Otx2 interact with the WD40 domain of Groucho/Tle corepressors. Mol Cell Biol. 2007;27:340-51 pubmed
    ..Interestingly, the association of Groucho with Otx2 is also required for the repression of Fgf8 in the MHB. Therefore Groucho/Tle family members appear to regulate key aspects in the MHB development of the vertebrate brain. ..
  32. Lobe C. Expression of the helix-loop-helix factor, Hes3, during embryo development suggests a role in early midbrain-hindbrain patterning. Mech Dev. 1997;62:227-37 pubmed
    ..Later in development, Hes3 is co-expressed with other neurogenic gene homologues in the developing central nervous system and epithelial cells undergoing mesenchyme induction. ..
  33. Dasen J, Martinez Barbera J, Herman T, Connell S, Olson L, Ju B, et al. Temporal regulation of a paired-like homeodomain repressor/TLE corepressor complex and a related activator is required for pituitary organogenesis. Genes Dev. 2001;15:3193-207 pubmed
  34. Kouwenhoven W, von Oerthel L, Smidt M. Pitx3 and En1 determine the size and molecular programming of the dopaminergic neuronal pool. PLoS ONE. 2017;12:e0182421 pubmed publisher
    ..Thus we reveal in this manuscript that regulated levels of Pitx3 and En1 control the size and rostral/caudal-identity of the mdDA neuronal population. ..
  35. Wu X, Xiao C, Li H, Tai Y, Zhang Q, Yang Y. Down-regulation of Transducin-Like Enhancer of Split protein 4 in hepatocellular carcinoma promotes cell proliferation and epithelial-Mesenchymal-Transition. Biochem Biophys Res Commun. 2016;477:161-6 pubmed publisher
    Transducin-Like Enhancer of Split protein 4 (TLE4) has been reported to be involved in some subsets of acute myeloid leukemia and colorectal cancer...
  36. Mallo M, Gendron Maguire M, Harbison M, Gridley T. Protein characterization and targeted disruption of Grg, a mouse gene related to the groucho transcript of the Drosophila Enhancer of split complex. Dev Dyn. 1995;204:338-47 pubmed
    ..No dosage-sensitive genetic interaction was detected between the Notch1 and Grg genes in mice heterozygous for a Notch1 mutant allele and homozygous for the Grg null mutation. ..
  37. McEvilly R, de Diaz M, Schonemann M, Hooshmand F, Rosenfeld M. Transcriptional regulation of cortical neuron migration by POU domain factors. Science. 2002;295:1528-32 pubmed
  38. Lee P, Taylor Jaffe K, Nordin K, Prasad M, Lander R, LaBonne C. SUMOylated SoxE factors recruit Grg4 and function as transcriptional repressors in the neural crest. J Cell Biol. 2012;198:799-813 pubmed publisher
    ..SoxE proteins, displacing coactivators CREB-binding protein/p300 while promoting the recruitment of a corepressor, Grg4. These data demonstrate that SoxE proteins can function as transcriptional repressors in a SUMO-dependent manner...
  39. Kraushar M, Thompson K, Wijeratne H, Viljetić B, Sakers K, Marson J, et al. Temporally defined neocortical translation and polysome assembly are determined by the RNA-binding protein Hu antigen R. Proc Natl Acad Sci U S A. 2014;111:E3815-24 pubmed publisher
    ..Our study identifies a crucial role for HuR in neocortical development as a translational gatekeeper for functionally related mRNA subgroups and polysomal protein specificity. ..
  40. Laing A, Lowell S, Brickman J. Gro/TLE enables embryonic stem cell differentiation by repressing pluripotent gene expression. Dev Biol. 2015;397:56-66 pubmed publisher
    ..Consistent with this view, we found that one of the Gro/TLE family, TLE4 is expressed heterogeneously in ESCs in a population that corresponds to a Nanog low subset of ESC culture...
  41. Di Giovannantonio L, Di Salvio M, Omodei D, Prakash N, Wurst W, Pierani A, et al. Otx2 cell-autonomously determines dorsal mesencephalon versus cerebellum fate independently of isthmic organizing activity. Development. 2014;141:377-88 pubmed publisher
    ..In this context, Otx2 is cell-autonomously required in the m1a sub-domain to suppress cerebellar fate and promote mesencephalic differentiation independently of the MHB organizing activity...
  42. McKenna W, Ortiz Londono C, Mathew T, Hoang K, Katzman S, Chen B. Mutual regulation between Satb2 and Fezf2 promotes subcerebral projection neuron identity in the developing cerebral cortex. Proc Natl Acad Sci U S A. 2015;112:11702-7 pubmed publisher
    ..Thus, Satb2 promotes the development of callosal and subcerebral neurons in a cell context-dependent manner. ..
  43. Zagami C, Stifani S. Molecular characterization of the mouse superior lateral parabrachial nucleus through expression of the transcription factor Runx1. PLoS ONE. 2010;5:e13944 pubmed publisher
    ..Based on the anatomical and molecular characteristics of the Runx1-expressing cells in the rostral hindbrain, we propose that Runx1 expression in this region of the mouse brain defines the superior lateral parabrachial nucleus. ..
  44. Sharma M, Brantley J, Vassmer D, Chaturvedi G, Baas J, Vanden Heuvel G. The homeodomain protein Cux1 interacts with Grg4 to repress p27 kip1 expression during kidney development. Gene. 2009;439:87-94 pubmed publisher
    ..Here we show that Cux1 directly interacts with the co-repressor Grg4 (Groucho 4), a known effector of Notch signaling...
  45. Puelles E, Acampora D, Lacroix E, Signore M, Annino A, Tuorto F, et al. Otx dose-dependent integrated control of antero-posterior and dorso-ventral patterning of midbrain. Nat Neurosci. 2003;6:453-60 pubmed
    ..We propose that this mechanism may provide both A-P and D-V positional information to neuronal precursors located within the midbrain. ..
  46. Hack I, Hellwig S, Junghans D, Brunne B, Bock H, Zhao S, et al. Divergent roles of ApoER2 and Vldlr in the migration of cortical neurons. Development. 2007;134:3883-91 pubmed
    ..We present evidence for divergent roles of the two reelin receptors Vldlr and ApoER2, with Vldlr mediating a stop signal for migrating neurons and ApoER2 being essential for the migration of late generated neocortical neurons. ..