Different E-box binding transcription factors, similar neuro-developmental defects: ZEB2 (Mowat-Wilson syndrome) and TCF4 (Pitt-Hopkins syndrome)

Abstract

ZEB2 and TCF4 are transcription factors (TFs) whose locations in embryos overlap in many sites and developmental phases, including in the forebrain and its cortical neurons. De novo mutations cause the phenotypically overlapping, haploinsufficient Mowat-Wilson (MOWS, in the ZEB2 gene) and Pitt-Hopkins (PTHS, in TCF4) syndromes, which currently cannot be cured. Mutant alleles have been mapped and defects documented (also in brain function) in MOWS and PTHS patients. Appropriately designed mouse models and cells derived from these, as well as cellular models including cultured pluripotent cells, enable investigating the genetic and molecular mechanisms underlying the developmental deficiencies that manifest after birth in the nervous systems and their multiple cell types, as well as those of organs other than the brain, in MOWS and PTHS. Biochemical analyses of cell type-specific transcriptomic changes in these perturbation models as compared to control cells, the identification of the intact-factor dependent and direct target genes, and of partner proteins including chromatin modulators, are revealing complex and multiple modes of action that eventually will explain target gene selectivity for these TFs. Both TFs have also been found to operate in acute and chronic diseases and cell-based repair processes after tissue or organ injury. In addition, the defective function also arises from their aberrant gene expression, which will require a deeper investigation of how the transcription of these TF genes is regulated. Furthermore, these two factors genetically and biochemically interact. This review combines the essentials and recent progress for both TFs for the first time, with a focus on MOWS and PTHS.

Keywords

E-box / Mowat-Wilson syndrome / neurodevelopment / Pitt-Hopkins syndrome / TCF4 / ZEB2

References

[1] Hempel A,Blyth M.DDD Collaborationdeletions and de novo mutations of sox11 are associated with a neurodevelopmental disorder with features of coffin-siris syndrome.J Med Genet2016;53:152-62 PMCID:PMC4789813

[2] Al-Naama N,Kino T.C₂H₂-type zinc finger proteins in brain development, neurodevelopmental, and other neuropsychiatric disorders: systematic literature-based analysis.Front Neurol2020;11:32 PMCID:PMC7034409

[3] Zhang K,Zhu J.Imbalance of excitatory/inhibitory neuron differentiation in neurodevelopmental disorders with an NR2F1 point mutation.Cell Rep2020;31:107521

[4] Blok L, Rousseau J, Twist J, et al; DDD study. CHD3 helicase domain mutations cause a neurodevelopmental syndrome with macrocephaly and impaired speech and language.Nat Commun2018;9:4619 PMCID:PMC6218476

[5] Yasin H,Langlois S.A distinct neurodevelopmental syndrome with intellectual disability, autism spectrum disorder, characteristic facies, and macrocephaly is caused by defects in CHD8.J Hum Genet2019;64:271-80

[6] Larrigan S,Fernandes A.Chromatin remodeling in the brain-a.NuRD22:4768 PMCID:PMC8125410

[7] Mossink B,Schubert D.The emerging role of chromatin remodelers in neurodevelopmental disorders: a developmental perspective.Cell Mol Life Sci2021;78:2517-63 PMCID:PMC8004494

[8] Birkhoff JC,Conidi A.ZEB2, the Mowat-Wilson syndrome transcription factor: confirmations, novel functions, and continuing surprises.Genes (Basel)2021;12:1037 PMCID:PMC8304685

[9] Teixeira JR,Carvalho VMA,Papes F.Transcription factor 4 and its association with psychiatric disorders.Transl Psychiatry2021;11:19 PMCID:PMC7791034

[10] Chen ES,Rosenfeld JA.Molecular convergence of neurodevelopmental disorders.Am J Hum Genet2014;95:490-508 PMCID:PMC4225591

[11] Sugathan A,Golzio C.CHD8 regulates neurodevelopmental pathways associated with autism spectrum disorder in neural progenitors.Proc Natl Acad Sci U S A2014;111:E4468-77 PMCID:PMC4210312

[12] Engelen E,Bryne JC.Sox2 cooperates with Chd7 to regulate genes that are mutated in human syndromes.Nat Genet2011;43:607-11

[13] Maussion G,Gigek CO.Investigation of genes important in neurodevelopment disorders in adult human brain.Hum Genet2015;134:1037-53

[14] Moen MJ,Brandsma JH.An interaction network of mental disorder proteins in neural stem cells.Transl Psychiatry2017;7:e1082 PMCID:PMC5416693

[15] Estruch SB,Quevedo M.Proteomic analysis of FOXP proteins reveals interactions between cortical transcription factors associated with neurodevelopmental disorders.Hum Mol Genet2018;

[16] Gabriele M,D’Agostino G.The chromatin basis of neurodevelopmental disorders: Rethinking dysfunction along the molecular and temporal axes.Prog Neuropsychopharmacol Biol Psychiatry2018;84:306-27

[17] Lewis EM.Development and disease in a dish: the epigenetics of neurodevelopmental disorders.Epigenomics2018;10:219-31 PMCID:PMC5810842

[18] Fallah MS,Robson CM.Impaired regulation of histone methylation and acetylation underlies specific neurodevelopmental disorders.Front Genet2020;11:613098 PMCID:PMC7820808

[19] Cogné B,Beauregard-Lacroix E.CAUSES StudyDeciphering Developmental Disorders studyMissense variants in the histone acetyltransferase complex component gene TRRAP cause autism and syndromic intellectual disability.Am J Hum Genet2019;104:530-41 PMCID:PMC6407527

[20] Bain G,Yao M,Gottlieb DI.Embryonic stem cells express neuronal properties in vitro.Dev Biol1995;168:342-57

[21] Okabe S,Spiro AC,Mckay RD.Development of neuronal precursor cells and functional postmitotic neurons from embryonic stem cells in vitro.Mechanisms of Development1996;59:89-102

[22] Zhang SC,Duncan ID,Thomson JA.In vitro differentiation of transplantable neural precursors from human embryonic stem cells.Nat Biotechnol2001;19:1129-33

[23] Ying QL,Griffiths D,Smith A.Conversion of embryonic stem cells into neuroectodermal precursors in adherent monoculture.Nat Biotechnol2003;21:183-6

[24] Peljto M.Programming embryonic stem cells to neuronal subtypes.Curr Opin Neurobiol2011;21:43-51 PMCID:PMC3050008

[25] Eiraku M.Self-formation of layered neural structures in three-dimensional culture of ES cells.Curr Opin Neurobiol2012;22:768-77

[26] Lancaster MA.Generation of cerebral organoids from human pluripotent stem cells.Nat Protoc2014;9:2329-40 PMCID:PMC4160653

[27] Zhang M,Pirozzi F,Wynshaw-Boris A.Highly efficient methods to obtain homogeneous dorsal neural progenitor cells from human and mouse embryonic stem cells and induced pluripotent stem cells.Stem Cell Res Ther2018;9:67 PMCID:PMC5856210

[28] Galiakberova AA.Neural stem cells and methods for their generation from induced pluripotent stem cells.in vitro8:815 PMCID:PMC7578226

[29] Hoffmann A.Single-Cell transcriptomics supports a role of.CHD822:3261 PMCID:PMC8004931

[30] Doostparast Torshizi A,Zhang H.Deconvolution of transcriptional networks identifies TCF4 as a master regulator in schizophrenia.Sci Adv2019;5:eaau4139 PMCID:PMC6739105

[31] Dries R,Coddens K.Integrative and perturbation-based analysis of the transcriptional dynamics of TGFβ/BMP system components in transition from embryonic stem cells to neural progenitors.Stem Cells2020;38:202-17 PMCID:PMC7027912

[32] Verschueren K,Collart C.SIP1, a novel zinc finger/homeodomain repressor, interacts with Smad proteins and binds to 5’-CACCT sequences in candidate target genes.J Biol Chem1999;274:20489-98

[33] Mowat DR,Cass DT.Hirschsprung disease, microcephaly, mental retardation, and characteristic facial features: delineation of a new syndrome and identification of a locus at chromosome 2q22-q23.J Med Genet1998;35:617-23 PMCID:PMC1051383

[34] Cacheux V,Kääriäinen H.Loss-of-function mutations in SIP1 Smad interacting protein 1 result in a syndromic Hirschsprung disease.Hum Mol Genet2001;10:1503-10

[35] Wakamatsu N,Yamada K.Mutations in SIP1, encoding Smad interacting protein-1, cause a form of Hirschsprung disease.Nat Genet2001;27:369-70

[36] Mowat DR,Goossens M.Mowat-Wilson syndrome.J Med Genet2003;40:305-10 PMCID:PMC1735450

[37] Mainardi P, Pastore G, Zweier C, Rauch A. Mowat-Wilson syndrome and mutation in the zinc finger homeo box 1B gene: a well defined clinical entity.J Med Genet2004;41:e16 PMCID:PMC1735678

[38] Ishihara N,Yamada Y.Clinical and molecular analysis of Mowat-Wilson syndrome associated with ZFHX1B mutations and deletions at 2q22-q24.1.J Med Genet2004;41:387-93 PMCID:PMC1735777

[39] Yamada K,Nomura N.Nonsense and frameshift mutations in ZFHX1B, encoding Smad-interacting protein 1, cause a complex developmental disorder with a great variety of clinical features.Am J Hum Genet2001;69:1178-85 PMCID:PMC1235530

[40] Wilson M,Dastot-Le Moal F.Further delineation of the phenotype associated with heterozygous mutations in ZFHX1B.Am J Med Genet A2003;119A:257-65

[41] Zweier C,Dufke A.Clinical and mutational spectrum of Mowat-Wilson syndrome.Eur J Med Genet2005;48:97-111

[42] Zweier C,Kraus C.Atypical ZFHX1B mutation associated with a mild Mowat-Wilson syndrome phenotype.Am J Med Genet A2006;140:869-72

[43] Garavelli L,Mainardi PC.Mowat-Wilson syndrome: facial phenotype changing with age: study of 19 Italian patients and review of the literature.Am J Med Genet A2009;149A:417-26

[44] Ivanovski I,Caraffi SG.Phenotype and genotype of 87 patients with Mowat-Wilson syndrome and recommendations for care.Genet Med2018;20:965-75

[45] Garavelli L,Caraffi SG.Neuroimaging findings in Mowat-Wilson syndrome: a study of 54 patients.Genet Med2017;19:691-700 PMCID:PMC5438871

[46] Ricci E,Garavelli L.Mowat Wilson Epilepsy Study GroupFurther delineation and long-term evolution of electroclinical phenotype in Mowat Wilson Syndrome. A longitudinal study in 40 individuals.Epilepsy Behav2021;124:108315

[47] Dastot-Le Moal F,Mowat D.ZFHX1B mutations in patients with Mowat-Wilson syndrome.Hum Mutat2007;28:313-21

[48] Heinritz W,Froster UG.A missense mutation in the ZFHX1B gene associated with an atypical Mowat-Wilson syndrome phenotype.Am J Med Genet A2006;140:1223-7

[49] Ghoumid J,Alavi-Naini SM.ZEB2 zinc-finger missense mutations lead to hypomorphic alleles and a mild Mowat-Wilson syndrome.Hum Mol Genet2013;22:2652-61

[50] Verstappen G,Michiels C.Atypical Mowat-Wilson patient confirms the importance of the novel association between ZFHX1B/SIP1 and NuRD corepressor complex.Hum Mol Genet2008;17:1175-83

[51] Wu LM,Conidi A.Zeb2 recruits HDAC-NuRD to inhibit notch and controls Schwann cell differentiation and remyelination.Nat Neurosci2016;19:1060-72 PMCID:PMC4961522

[52] Birkhoff JC,Kolovos P.Targeted chromatin conformation analysis identifies novel distal neural enhancers of ZEB2 in pluripotent stem cell differentiation.Hum Mol Genet2020;29:2535-50 PMCID:PMC7471508

[53] Huang X,Kim S.Differential usage of transcriptional repressor Zeb2 enhancers distinguishes adult and embryonic hematopoiesis.Immunity2021;54:1417-1432.e7 PMCID:PMC8282756

[54] Pitt D.A syndrome of mental retardation, wide mouth and intermittent overbreathing.Aust Paediatr J1978;14:182-4

[55] Amiel J,de Pontual L.Mutations in TCF4, encoding a class I basic helix-loop-helix transcription factor, are responsible for Pitt-Hopkins syndrome, a severe epileptic encephalopathy associated with autonomic dysfunction.Am J Hum Genet2007;80:988-93 PMCID:PMC1852736

[56] Brockschmidt A,Ryu S.Severe mental retardation with breathing abnormalities (Pitt-Hopkins syndrome) is caused by haploinsufficiency of the neuronal bHLH transcription factor TCF4.Hum Mol Genet2007;16:1488-94

[57] Zweier C,Hoyer J.Haploinsufficiency of TCF4 causes syndromal mental retardation with intermittent hyperventilation (Pitt-Hopkins syndrome).Am J Hum Genet2007;80:994-1001 PMCID:PMC1852727

[58] Marangi G.Pitt-Hopkins Syndrome and Differential Diagnosis: a Molecular and Clinical Challenge.J Pediatr Genet2015;4:168-76 PMCID:PMC4918722

[59] Whalen S,Gaillon T.Novel comprehensive diagnostic strategy in Pitt-Hopkins syndrome: clinical score and further delineation of the TCF4 mutational spectrum.Hum Mutat2012;33:64-72

[60] Fierro JA, Avina DA. Pitt-Hopkins syndrome: mental retardation, psychomotor and developmental delays with facial dysmorphism.J Pediatr Genet2014;3:141-5 PMCID:PMC5020997

[61] Mary L,Schaefer E.Disease-causing variants in TCF4 are a frequent cause of intellectual disability: lessons from large-scale sequencing approaches in diagnosis.Eur J Hum Genet2018;26:996-1006 PMCID:PMC6018712

[62] Goodspeed K,Morris MA.Pitt-Hopkins syndrome: a review of current literature, clinical approach, and 23-patient case series.J Child Neurol2018;33:233-44 PMCID:PMC5922265

[63] Remacle JE,Lerchner W.New mode of DNA binding of multi-zinc finger transcription factors: deltaEF1 family members bind with two hands to two target sites.EMBO J1999;18:5073-84 PMCID:PMC1171578

[64] Birkhoff JC,Brouwer RWW.Zeb2 DNA-binding sites in ES cell derived neuroprogenitor cells reveal autoregulation and align with neurodevelopmental knockout mouse and disease phenotypes.bioRχiv2021;

[65] Murre C,Baltimore D.A new DNA binding and dimerization motif in immunoglobulin enhancer binding, daughterless, MYOD, and MYC proteins.Cell1989;56:777-83

[66] Conidi A,Leslie K.Four amino acids within a tandem QxVx repeat in a predicted extended α-helix of the Smad-binding domain of Sip1 are necessary for binding to activated Smad proteins.PLoS One2013;8:e76733 PMCID:PMC3795639

[67] Sepp M,Eesmaa A,Timmusk T.Functional diversity of human basic helix-loop-helix transcription factor TCF4 isoforms generated by alternative 5’ exon usage and splicing.PLoS One2011;6:e22138 PMCID:PMC3137626

[68] Nurm K,Castany-Pladevall C.Isoform-Specific Reduction of the Basic Helix-Loop-Helix Transcription Factor TCF4 Levels in Huntington’s Disease.eNeuro2021;8:ENEURO PMCID:PMC8519306

[69] Chen HY,Maher BJ.Molecular and cellular function of transcription factor 4 in Pitt-Hopkins syndrome.Dev Neurosci2021;43:159-67 PMCID:PMC8440355

[70] Maduro V,Cherukuri PF.Complex translocation disrupting TCF4 and altering TCF4 isoform expression segregates as mild autosomal dominant intellectual disability.Orphanet J Rare Dis2016;11:62 PMCID:PMC4868023

[71] Bedeschi MF,Calvello MR.Impairment of different protein domains causes variable clinical presentation within Pitt-Hopkins syndrome and suggests intragenic molecular syndromology of TCF4.Eur J Med Genet2017;60:565-71

[72] Forrest M,Doyle AM.Functional analysis of TCF4 missense mutations that cause Pitt-Hopkins syndrome.Hum Mutat2012;33:1676-86

[73] Wang LH.E proteins and ID proteins: helix-loop-helix partners in development and disease.Dev Cell2015;35:269-80 PMCID:PMC4684411

[74] Yang J,Li J.Structural basis for preferential binding of human TCF4 to DNA containing 5-carboxylcytosine.Nucleic Acids Res2019;47:8375-87 PMCID:PMC6895265

[75] Massari ME,Pray-grant MG.A conserved motif present in a class of helix-loop-helix proteins activates transcription by direct recruitment of the SAGA complex.Molecular Cell1999;4:63-73

[76] Bayly R,Currie RA.E2A-PBX1 interacts directly with the KIX domain of CBP/p300 in the induction of proliferation in primary hematopoietic cells.J Biol Chem2004;279:55362-71

[77] Zhang J,Yamamura S,Roeder RG.E protein silencing by the leukemogenic AML1-ETO fusion protein.Science2004;305:1286-9

[78] Quevedo M,Dekker MR.Mediator complex interaction partners organize the transcriptional network that defines neural stem cells.Nat Commun2019;10:2669 PMCID:PMC6573065

[79] van den Berghe V,Vandesande B.Directed migration of cortical interneurons depends on the cell-autonomous action of Sip1.Neuron2013;77:70-82

[80] Stryjewska A,Pieters T.Zeb2 regulates cell fate at the exit from epiblast state in mouse embryonic stem cells.Stem Cells2017;35:611-25 PMCID:PMC5396376

[81] van Helden MJ,Daussy C.Terminal NK cell maturation is controlled by concerted actions of T-bet and Zeb2 and is essential for melanoma rejection.J Exp Med2015;212:2015-25 PMCID:PMC4647267

[82] Wang J,Benyoucef A.Interplay between the EMT transcription factors ZEB1 and ZEB2 regulates hematopoietic stem and progenitor cell differentiation and hematopoietic lineage fidelity.PLoS Biol2021;19:e3001394 PMCID:PMC8489726

[83] Dowen JM,Hnisz D.Control of cell identity genes occurs in insulated neighborhoods in mammalian chromosomes.Cell2014;159:374-87 PMCID:PMC4197132

[84] Benito-Kwiecinski S,Sutcliffe M.An early cell shape transition drives evolutionary expansion of the human forebrain.Cell2021;184:2084-2102.e19 PMCID:PMC8054913

[85] Kim H,Ochandarena NE.Region and cell type distribution of TCF4 in the postnatal mouse brain.Front Neuroanat2020;14:42 PMCID:PMC7379912

[86] Lennertz L,Wagner M.Novel schizophrenia risk gene TCF4 influences verbal learning and memory functioning in schizophrenia patients.Neuropsychobiology2011;63:131-6

[87] Quednow BB,Mössner R.The schizophrenia risk allele C of the TCF4 rs9960767 polymorphism disrupts sensorimotor gating in schizophrenia spectrum and healthy volunteers.J Neurosci2011;31:6684-91 PMCID:PMC6632862

[88] Jung M,Tschaikowsky T.Analysis of the expression pattern of the schizophrenia-risk and intellectual disability gene TCF4 in the developing and adult brain suggests a role in development and plasticity of cortical and hippocampal neurons.Mol Autism2018;9:20 PMCID:PMC5863811

[89] Sripathy SR,Moses RL.Generation of 10 patient-specific induced pluripotent stem cells (iPSCs) to model Pitt-Hopkins syndrome.Stem Cell Res2020;48:102001 PMCID:PMC7592084

[90] Gheldof A,van Roy F,Berx G.Evolutionary functional analysis and molecular regulation of the ZEB transcription factors.Cell Mol Life Sci2012;69:2527-41

[91] Hegarty SV,O’Keeffe GW.Zeb2: a multifunctional regulator of nervous system development.Prog Neurobiol2015;132:81-95

[92] Epifanova E,Newman AG.Role of Zeb2/Sip1 in neuronal development.Brain Res2019;1705:24-31

[93] Scott CL.ZEBs: novel players in immune cell development and function.Trends Immunol2019;40:431-46

[94] Higashi Y,Nelles L.Generation of the floxed allele of the SIP1 (Smad-interacting protein 1) gene for Cre-mediated conditional knockout in the mouse.Genesis2002;32:82-4

[95] Seuntjens E,Miquelajauregui A.Sip1 regulates sequential fate decisions by feedback signaling from postmitotic neurons to progenitors.Nat Neurosci2009;12:1373-80

[96] McKinsey GL,Trzcinski B.Dlx1&2-dependent expression of Zfhx1b (Sip1, Zeb2) regulates the fate switch between cortical and striatal interneurons.Neuron2013;77:83-98 PMCID:PMC3547499

[97] Deryckere A,Dries R.Multifaceted actions of Zeb2 in postnatal neurogenesis from the ventricular-subventricular zone to the olfactory bulb.Development2020;147:dev184861

[98] Vivinetto AL,Goldberg DC.Zeb2 is a regulator of astrogliosis and functional recovery after CNS injury.Cell Rep2020;31:107834 PMCID:PMC7416489

[99] Quintes S,Ebert M.Zeb2 is essential for Schwann cell differentiation, myelination and nerve repair.Nat Neurosci2016;19:1050-9 PMCID:PMC4964942

[100] Boland BS,Tsai MS.Heterogeneity and clonal relationships of adaptive immune cells in ulcerative colitis revealed by single-cell analyses.Sci Immunol2020;5:eabb4432 PMCID:PMC7733868

[101] Gladka MM,Molenaar B.Cardiomyocytes stimulate angiogenesis after ischemic injury in a ZEB2-dependent manner.Nat Commun2021;12:84 PMCID:PMC7782784

[102] de Haan W,Apelt K.Endothelial Zeb2 preserves the hepatic angioarchitecture and protects against liver fibrosis.Cardiovasc Res2022;118:1262-75 PMCID:PMC8953454

[103] Vandamme N,Bruneel K.The EMT transcription factor ZEB2 promotes proliferation of primary and metastatic melanoma while suppressing an invasive, mesenchymal-like phenotype.Cancer Res2020;80:2983-95

[104] Turovskaya MV,Zinchenko VP.Sip-1 mutations cause disturbances in the activity of NMDA- and AMPA-, but not kainate receptors of neurons in the cerebral cortex.Neurosci Lett2017;650:180-6

[105] Jeub M,Pradier B.The transcription factor Smad-interacting protein 1 controls pain sensitivity via modulation of DRG neuron excitability.Pain2011;152:2384-98

[106] Pradier B,Markert A.Smad-interacting protein 1 affects acute and tonic, but not chronic pain.Eur J Pain2014;18:249-57

[107] Khan RAW,Wang M.A new risk locus in the ZEB2 gene for schizophrenia in the Han Chinese population.Prog Neuropsychopharmacol Biol Psychiatry2016;66:97-103

[108] Takagi T,Matsui F,Higashi Y.De novo inbred heterozygous Zeb2/Sip1 mutant mice uniquely generated by germ-line conditional knockout exhibit craniofacial, callosal and behavioral defects associated with Mowat-Wilson syndrome.Hum Mol Genet2015;24:6390-402

[109] Rannals MD.Molecular mechanisms of transcription factor 4 in Pitt hopkins syndrome.Curr Genet Med Rep2017;5:1-7 PMCID:PMC6376960

[110] Braun K,Wittmann MT.Enriched environment ameliorates adult hippocampal neurogenesis deficits in Tcf4 haploinsufficient mice.BMC Neurosci2020;21:50 PMCID:PMC7684915

[111] Praag H, Kempermann G, Gage FH. Neural consequences of environmental enrichment.Nat Rev Neurosci2000;1:191-8

[112] Kennedy AJ,Paulukaitis BS.Tcf4 regulates synaptic plasticity, DNA methylation, and memory function.Cell Rep2016;16:2666-85 PMCID:PMC5710002

[113] Sepp M,Timmusk T.Pitt-Hopkins syndrome-associated mutations in TCF4 lead to variable impairment of the transcription factor function ranging from hypomorphic to dominant-negative effects.Hum Mol Genet2012;21:2873-88

[114] Flora A,Thaller C.The E-protein Tcf4 interacts with Math1 to regulate differentiation of a specific subset of neuronal progenitors.Proc Natl Acad Sci U S A2007;104:15382-7 PMCID:PMC1978485

[115] Fischer B,Hurtado-Chong A.E-proteins orchestrate the progression of neural stem cell differentiation in the postnatal forebrain.Neural Dev2014;9:23 PMCID:PMC4274746

[116] Li H,Morozov YM.Disruption of TCF4 regulatory networks leads to abnormal cortical development and mental disabilities.Mol Psychiatry2019;24:1235-46

[117] Mesman S,Smidt MP.Tcf4 is required for correct brain development during embryogenesis.Mol Cell Neurosci2020;106:103502

[118] Thaxton C,Clark EP.Common pathophysiology in multiple mouse models of Pitt-Hopkins syndrome.J Neurosci2018;38:918-36 PMCID:PMC5783968

[119] Schoof M,Harrison L.The basic helix-loop-helix transcription factor TCF4 impacts brain architecture as well as neuronal morphology and differentiation.Eur J Neurosci2020;51:2219-35

[120] Phan BN,Davis BA.A myelin-related transcriptomic profile is shared by Pitt-Hopkins syndrome models and human autism spectrum disorder.Nat Neurosci2020;23:375-85 PMCID:PMC7065955

[121] Weng Q,Wang H.Dual-mode modulation of Smad signaling by Smad-interacting protein Sip1 is required for myelination in the central nervous system.Neuron2012;73:713-28 PMCID:PMC3293152

[122] Zhang Y,Wang Y.Survival control of oligodendrocyte progenitor cells requires the transcription factor 4 during olfactory bulb development.Cell Death Dis2021;12:91 PMCID:PMC7813844

[123] Cisse B,Lehner M.Transcription factor E2-2 is an essential and specific regulator of plasmacytoid dendritic cell development.Cell2008;135:37-48 PMCID:PMC2631034

[124] Hill MJ,Navarrete K.Knockdown of the schizophrenia susceptibility gene.TCF442:181-8 PMCID:PMC5403663

[125] Forrest MP,Martin-Rendon E.Knockdown of human TCF4 affects multiple signaling pathways involved in cell survival, epithelial to mesenchymal transition and neuronal differentiation.PLoS One2013;8:e73169 PMCID:PMC3751932

[126] Chen T,Zhang Y.Tcf4 controls neuronal migration of the cerebral cortex through regulation of bmp7.Front Mol Neurosci2016;9:94 PMCID:PMC5046712

[127] Allen HF,Kutateladze TG.The NuRD architecture.Cell Mol Life Sci2013;70:3513-24 PMCID:PMC3652912

[128] Kloet SL,Makowski M.Towards elucidating the stability, dynamics and architecture of the nucleosome remodeling and deacetylase complex by using quantitative interaction proteomics.FEBS J2015;282:1774-85

[129] Torchy MP,Klaholz BP.Structure and function insights into the NuRD chromatin remodeling complex.Cell Mol Life Sci2015;72:2491-507

[130] Fröb F.The role of chromatin remodeling complexes in Schwann cell development.Glia2020;68:1596-603

[131] D’Souza L,Muralidharan B.Chromatin remodelling complexes in cerebral cortex development and neurodevelopmental disorders.Neurochem Int2021;147:105055 PMCID:PMC7611358

[132] Benayoun BA,Ucar D.H3K4me3 breadth is linked to cell identity and transcriptional consistency.Cell2014;158:673-88 PMCID:PMC4137894

[133] Chen K,Wu D.Broad H3K4me3 is associated with increased transcription elongation and enhancer activity at tumor-suppressor genes.Nat Genet2015;47:1149-57 PMCID:PMC4780747

[134] Miquelajauregui A,Polyakov A.Smad-interacting protein-1 (Zfhx1b) acts upstream of Wnt signaling in the mouse hippocampus and controls its formation.Proc Natl Acad Sci U S A2007;104:12919-24 PMCID:PMC1929013

[135] Kotter MR,Hartung HP.Enhancing remyelination in disease-can we wrap it up?.Brain2011;134:1882-900

[136] de Putte T, Francis A, Nelles L, van Grunsven LA, Huylebroeck D. Neural crest-specific removal of Zfhx1b in mouse leads to a wide range of neurocristopathies reminiscent of Mowat-Wilson syndrome.Hum Mol Genet2007;16:1423-36

[137] Szu J,Jiang P.Impact of the Olig Family on Neurodevelopmental Disorders.Front Neurosci2021;15:659601 PMCID:PMC8042229

[138] Hennig KM,Zhao WN.WNT/β-catenin pathway and epigenetic mechanisms regulate the pitt-hopkins syndrome and schizophrenia risk gene.TCF43:53-71 PMCID:PMC5582445

[139] Brabletz S,Brabletz T.Dynamic EMT: a multi-tool for tumor progression.EMBO J2021;40:e108647 PMCID:PMC8441439

[140] Chen H,Huang C.Prognostic significance of ZEB1 and ZEB2 in digestive cancers: a cohort-based analysis and secondary analysis.Oncotarget2017;8:31435-48 PMCID:PMC5458220