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Transcriptional Regulation by FOXP1, FOXP2, and FOXP4 Dimerization

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Abstract

FOXP1, FOXP2, and FOXP4 are three members of the FOXP gene subfamily of transcription factors involved in the development of the central nervous system. Previous studies have shown that the transcriptional activity of FOXP1/2/4 is regulated by homo- and heterodimerization. However, their transcriptional gene targets in the developing brain are still largely unknown. FOXP2 regulates the expression of many genes important in embryonic development, including WNT and Notch signaling pathways. In this study, we investigate whether dimerization of FOXP1/2/4 leads to differential expression of ten known FOXP2 target genes (CER1, SFRP4, WISP2, PRICKLE1, NCOR2, SNW1, NEUROD2, PAX3, EFNB3, and SLIT1). FOXP1/2/4 open-reading frames were stably transfected into HEK293 cells, and the expression level of these FOXP2 target genes was quantified using real-time polymerase chain reaction. Our results revealed that the specific combination of FOXP1/2/4 dimers regulates transcription of various FOXP2 target genes involved in early neuronal development.

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References

  • Artavanis-Tsakonas S, Rand MD, Lake RJ (1999) Notch signaling: cell fate control and signal integration in development. Science 284:770–776

    Article  CAS  PubMed  Google Scholar 

  • Bowers JM, Konopka G (2012) The role of the FOXP family of transcription factors in ASD. Dis Markers 33:251–260

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Fisher SE, Scharff C (2009) FOXP2 as a molecular window into speech and language. Trends Genet 25:166–177

    Article  CAS  PubMed  Google Scholar 

  • Franklin A, Kao A, Tapscott S, Unis A (2001) NeuroD homologue expression during cortical development in the human brain. J Child Neurol 16:849–853

    Article  CAS  PubMed  Google Scholar 

  • Hamdan FF, Daoud H, Rochefort D, Piton A, Gauthier J, Langlois M, Foomani G, Dobrzeniecka S, Krebs MO, Joober R, Lafreniere RG, Lacaille JC, Mottron L, Drapeau P, Beauchamp MH, Phillips MS, Fombonne E, Rouleau GA, Michaud JL (2010) De novo mutations in FOXP1 in cases with intellectual disability, autism, and language impairment. Am J Hum Genet 87:671–678

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Horn D, Kapeller J, Rivera-Brugues N, Moog U, Lorenz-Depiereux B, Eck S, Hempel M, Wagenstaller J, Gawthrope A, Monaco AP, Bonin M, Riess O, Wohlleber E, Illig T, Bezzina CR, Franke A, Spranger S, Villavicencio-Lorini P, Seifert W, Rosenfeld J, Klopocki E, Rappold GA, Strom TM (2010) Identification of FOXP1 deletions in three unrelated patients with mental retardation and significant speech and language deficits. Hum Mutat 31:E1851–1860

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Jepsen K, Solum D, Zhou T, McEvilly RJ, Kim HJ, Glass CK, Hermanson O, Rosenfeld MG (2007) SMRT-mediated repression of an H3K27 demethylase in progression from neural stem cell to neuron. Nature 450:415–419

    Article  CAS  PubMed  Google Scholar 

  • Jepsen K, Gleiberman AS, Shi C, Simon DI, Rosenfeld MG (2008) Cooperative regulation in development by SMRT and FOXP1. Genes Dev 22:740–745

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Konopka G, Bomar JM, Winden K, Coppola G, Jonsson ZO, Gao F, Peng S, Preuss TM, Wohlschlegel JA, Geschwind DH (2009) Human-specific transcriptional regulation of CNS development genes by FOXP2. Nature 462:213–217

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Lai CS, Fisher SE, Hurst JA, Vargha-Khadem F, Monaco AP (2001) A forkhead-domain gene is mutated in a severe speech and language disorder. Nature 413:519–523

    Article  CAS  PubMed  Google Scholar 

  • Li S, Weidenfeld J, Morrisey EE (2004) Transcriptional and DNA binding activity of the Foxp1/2/4 family is modulated by heterotypic and homotypic protein interactions. Mol Cell Biol 24:809–822

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Lu MM, Li S, Yang H, Morrisey EE (2002) Foxp4: a novel member of the Foxp subfamily of winged-helix genes co-expressed with Foxp1 and Foxp2 in pulmonary and gut tissues. Mech Dev 119(Suppl 1):S197–S202

    Article  PubMed  Google Scholar 

  • MacDermot KD, Bonora E, Sykes N, Coupe AM, Lai CS, Vernes SC, Vargha-Khadem F, McKenzie F, Smith RL, Monaco AP, Fisher SE (2005) Identification of FOXP2 truncation as a novel cause of developmental speech and language deficits. Am J Hum Genet 76:1074–1080

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Olson JM, Asakura A, Snider L, Hawkes R, Strand A, Stoeck J, Hallahan A, Pritchard J, Tapscott SJ (2001) NeuroD2 is necessary for development and survival of central nervous system neurons. Dev Biol 234:174–187

    Article  CAS  PubMed  Google Scholar 

  • O'Roak BJ, Deriziotis P, Lee C, Vives L, Schwartz JJ, Girirajan S, Karakoc E, Mackenzie AP, Ng SB, Baker C, Rieder MJ, Nickerson DA, Bernier R, Fisher SE, Shendure J, Eichler EE (2011) Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations. Nat Genet 43:585–589

    Article  PubMed Central  PubMed  Google Scholar 

  • Shu W, Yang H, Zhang L, Lu MM, Morrisey EE (2001) Characterization of a new subfamily of winged-helix/forkhead (Fox) genes that are expressed in the lung and act as transcriptional repressors. J Biol Chem 276:27488–27497

    Article  CAS  PubMed  Google Scholar 

  • Spiteri E, Konopka G, Coppola G, Bomar J, Oldham M, Ou J, Vernes SC, Fisher SE, Ren B, Geschwind DH (2007) Identification of the transcriptional targets of FOXP2, a gene linked to speech and language, in developing human brain. Am J Hum Genet 81:1144–1157

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Swinkels ME, Simons A, Smeets DF, Vissers LE, Veltman JA, Pfundt R, de Vries BB, Faas BH, Schrander-Stumpel CT, McCann E, Sweeney E, May P, Draaisma JM, Knoers NV, van Kessel AG, van Ravenswaaij-Arts CM (2008) Clinical and cytogenetic characterization of 13 Dutch patients with deletion 9p syndrome: Delineation of the critical region for a consensus phenotype. Am J Med Genet A 146A:1430–1438

    Article  CAS  PubMed  Google Scholar 

  • Takahashi K, Liu FC, Hirokawa K, Takahashi H (2008a) Expression of Foxp4 in the developing and adult rat forebrain. J Neurosci Res 86:3106–3116

    Article  CAS  PubMed  Google Scholar 

  • Takahashi K, Liu FC, Oishi T, Mori T, Higo N, Hayashi M, Hirokawa K, Takahashi H (2008b) Expression of FOXP2 in the developing monkey forebrain: comparison with the expression of the genes FOXP1, PBX3, and MEIS2. J Comp Neurol 509:180–189

    Article  CAS  PubMed  Google Scholar 

  • Takahashi H, Takahashi K, Liu FC (2009) FOXP genes, neural development, speech and language disorders. Adv Exp Med Biol 665:117–129

    Article  CAS  PubMed  Google Scholar 

  • Talkowski ME, Rosenfeld JA, Blumenthal I, Pillalamarri V, Chiang C, Heilbut A, Ernst C, Hanscom C, Rossin E, Lindgren AM, Pereira S, Ruderfer D, Kirby A, Ripke S, Harris DJ, Lee JH, Ha K, Kim HG, Solomon BD, Gropman AL, Lucente D, Sims K, Ohsumi TK, Borowsky ML, Loranger S, Quade B, Lage K, Miles J, Wu BL, Shen Y, Neale B, Shaffer LG, Daly MJ, Morton CC, Gusella JF (2012) Sequencing chromosomal abnormalities reveals neurodevelopmental loci that confer risk across diagnostic boundaries. Cell 149:525–537

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Teramitsu I, Kudo LC, London SE, Geschwind DH, White SA (2004) Parallel FoxP1 and FoxP2 expression in songbird and human brain predicts functional interaction. J Neurosci 24:3152–3163

    Article  CAS  PubMed  Google Scholar 

  • Vallipuram J, Grenville J, Crawford DA (2009) The E646D-ATP13A4 mutation associated with autism reveals a defect in calcium regulation. Cell Mol Neurobiol 30:233–246

    Article  Google Scholar 

  • Vernes SC, Spiteri E, Nicod J, Groszer M, Taylor JM, Davies KE, Geschwind DH, Fisher SE (2007) High-throughput analysis of promoter occupancy reveals direct neural targets of FOXP2, a gene mutated in speech and language disorders. Am J Hum Genet 81:1232–1250

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Vernes SC, Newbury DF, Abrahams BS, Winchester L, Nicod J, Groszer M, Alarcon M, Oliver PL, Davies KE, Geschwind DH, Monaco AP, Fisher SE (2008) A functional genetic link between distinct developmental language disorders. N Engl J Med 359:2337–2345

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Vernes SC, Oliver PL, Spiteri E, Lockstone HE, Puliyadi R, Taylor JM, Ho J, Mombereau C, Brewer A, Lowy E, Nicod J, Groszer M, Baban D, Sahgal N, Cazier JB, Ragoussis J, Davies KE, Geschwind DH, Fisher SE (2011) Foxp2 regulates gene networks implicated in neurite outgrowth in the developing brain. PLoS Genet 7:e1002145

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Weingarten LS, Dave H, Li H, Crawford DA (2012) Developmental expression of P5 ATPase mRNA in the mouse. Cell Mol Biol Lett 17:153–170

    Article  CAS  PubMed  Google Scholar 

  • Wilke SA, Hall BJ, Antonios JK, Denardo LA, Otto S, Yuan B, Chen F, Robbins EM, Tiglio K, Williams ME, Qiu Z, Biederer T, Ghosh A (2012) NeuroD2 regulates the development of hippocampal mossy fiber synapses. Neural Dev 7:9

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Xu NJ, Sun S, Gibson JR, Henkemeyer M (2011) A dual shaping mechanism for postsynaptic ephrin-B3 as a receptor that sculpts dendrites and synapses. Nat Neurosci 14:1421–1429

    Article  CAS  PubMed Central  PubMed  Google Scholar 

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Acknowledgments

This study was supported by the generosity of the Alva Foundation, Dean’s Health Research Catalyst Award (York University), and the Natural Sciences and Engineering Research Council of Canada (NSERC).

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Authors and Affiliations

  1. School of Kinesiology and Health Science, York University, Toronto, Ontario, Canada

    Cora Sin, Hongyan Li & Dorota A. Crawford

  2. Neuroscience Graduate Diploma Program, York University, Toronto, Ontario, Canada

    Cora Sin & Dorota A. Crawford

  3. Department of Biology, Faculty of Health, York University, 4700 Keele Street, Toronto, Ontario, M3J-1P3, Canada

    Dorota A. Crawford

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  1. Cora Sin
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  2. Hongyan Li
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  3. Dorota A. Crawford
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Correspondence to Dorota A. Crawford.

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Sin, C., Li, H. & Crawford, D.A. Transcriptional Regulation by FOXP1, FOXP2, and FOXP4 Dimerization. J Mol Neurosci 55, 437–448 (2015). https://doi.org/10.1007/s12031-014-0359-7

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  • DOI: https://doi.org/10.1007/s12031-014-0359-7

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