Genetic studies of the last decades strongly indicated that generation of particular retinal cell types is governed by gene regulatory networks of transcription factors and their target genes. The paired and homeodomain transcription factor Pax6 plays a pivotal role in retinal development as its inactivation in the retinal progenitor cell population leads to abolished differentiation of all retinal cell types. However, until now, only a few transcription factors operating downstream of Pax6 responsible for generation of individual retinal cell types have been identified. In this study, we identified two transcription factors of the Onecut family, Onecut1 and Onecut2, as Pax6 downstream-acting factors. Onecut1 and Onecut2 were previously shown to be expressed in developing horizontal cells, retinal ganglion cells and cone photoreceptors; however, their role in differentiation of these cell types is poorly understood. In this study, we show that the horizontal cell genesis is severely disturbed in Onecut-deficient retinae. In single Onecut1 and Onecut2 mutants, the number of horizontal cells is dramatically reduced while horizontal cells are completely missing in the Onecut1/Onecut2 compound mutant. Analysis of genes involved in the horizontal cell genesis such as Foxn4, Ptf1a, Prox1 and Lim1 showed that although horizontal cells are initially formed, they are not maintained in Onecut-deficient retinae. Taken together, this study suggests the model in which Pax6 regulates the maintenance of horizontal cells through the activation of Onecut1 and Onecut2 transcription factors.

• Keywords
• Horizontal cell, Onecut, Pax6, Retina,
• MeSH
• Retinal Cone Photoreceptor Cells metabolism   MeSH
• Phenotype MeSH
• Hepatocyte Nuclear Factor 6 metabolism   MeSH
• Homeodomain Proteins metabolism   MeSH
• In Situ Hybridization MeSH
• Stem Cells cytology   MeSH
• Molecular Sequence Data MeSH
• Mutation MeSH
• Mice, Transgenic MeSH
• Mice MeSH
• Eye Proteins metabolism   MeSH
• Repressor Proteins metabolism   MeSH
• Retina embryology   metabolism   MeSH
• Base Sequence MeSH
• Sequence Homology, Nucleic Acid MeSH
• PAX6 Transcription Factor MeSH
• Paired Box Transcription Factors metabolism   MeSH
• Transcription Factors metabolism   MeSH
• Binding Sites MeSH
• Gene Expression Regulation, Developmental MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Hepatocyte Nuclear Factor 6 MeSH
• Homeodomain Proteins MeSH
• Eye Proteins MeSH
• Onecut1 protein, mouse MeSH Browser
• ONECUT2 protein, mouse MeSH Browser
• Pax6 protein, mouse MeSH Browser
• Repressor Proteins MeSH
• PAX6 Transcription Factor MeSH
• Paired Box Transcription Factors MeSH
• Transcription Factors MeSH

Genome duplication leads to an emergence of gene paralogs that are essentially free to undergo the process of neofunctionalization, subfunctionalization or degeneration (gene loss). Onecut1 (Oc1) and Onecut2 (Oc2) transcription factors, encoded by paralogous genes in mammals, are expressed in precursors of horizontal cells (HCs), retinal ganglion cells and cone photoreceptors. Previous studies have shown that ablation of either Oc1 or Oc2 gene in the mouse retina results in a decreased number of HCs, while simultaneous deletion of Oc1 and Oc2 leads to a complete loss of HCs. Here we study the genetic redundancy between Oc1 and Oc2 paralogs and focus on how the dose of Onecut transcription factors influences abundance of individual retinal cell types and overall retina physiology. Our data show that reducing the number of functional Oc alleles in the developing retina leads to a gradual decrease in the number of HCs, progressive thinning of the outer plexiform layer and diminished electrophysiology responses. Taken together, these observations indicate that in the context of HC population, the alleles of Oc1/Oc2 paralogous genes are mutually interchangeable, function additively to support proper retinal function and their molecular evolution does not follow one of the typical routes after gene duplication.

• MeSH
• Alleles MeSH
• Amacrine Cells metabolism   pathology   MeSH
• Retinal Bipolar Cells metabolism   pathology   MeSH
• Retinal Cone Photoreceptor Cells metabolism   pathology   MeSH
• Ependymoglial Cells metabolism   pathology   MeSH
• Genetic Loci MeSH
• Genotype MeSH
• Hepatocyte Nuclear Factor 6 genetics   metabolism   MeSH
• Homeodomain Proteins genetics   metabolism   MeSH
• Mice, Transgenic MeSH
• Mice MeSH
• Eye growth & development   pathology   MeSH
• Retina cytology   pathology   physiology   MeSH
• Retinal Ganglion Cells cytology   metabolism   MeSH
• Transcription Factors genetics   metabolism   MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Hepatocyte Nuclear Factor 6 MeSH
• Homeodomain Proteins MeSH
• Onecut1 protein, mouse MeSH Browser
• ONECUT2 protein, mouse MeSH Browser
• Transcription Factors MeSH

Commensal microbiota contribute to gut homeostasis by inducing transcription of mucosal genes. Analysis of the impact of various microbiota on intestinal tissue provides an important insight into the function of this organ. We used cDNA microarrays to determine the gene expression signature of mucosa isolated from the small intestine and colon of germ-free (GF) mice and animals monoassociated with two E. coli strains. The results were compared to the expression data obtained in conventionally reared (CR) mice. In addition, we analyzed gene expression in colon organoids derived from CR, GF, and monoassociated animals. The analysis revealed that the complete absence of intestinal microbiota mainly affected the mucosal immune system, which was not restored upon monoassociation. The most important expression changes observed in the colon mucosa indicated alterations in adipose tissue and lipid metabolism. In the comparison of differentially expressed genes in the mucosa or organoids obtained from GF and CR mice, only six genes were common for both types of samples. The results show that the increased expression of the angiopoietin-like 4 (Angptl4) gene encoding a secreted regulator of lipid metabolism indicates the GF status.

• Keywords
• Enricher tool, Onecut2, expression profiling, microbiota, monoassociation,
• MeSH
• Biomarkers metabolism   MeSH
• Escherichia coli physiology   MeSH
• Germ-Free Life genetics   MeSH
• Immune System metabolism   MeSH
• Colon metabolism   MeSH
• Microbiota MeSH
• Mice, Inbred BALB C MeSH
• Organoids metabolism   MeSH
• Gene Expression Regulation MeSH
• Immunity, Mucosal MeSH
• Gene Expression Profiling * MeSH
• Intestinal Mucosa metabolism   MeSH
• Animals MeSH
• Check Tag
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Biomarkers MeSH

Pre-B-cell leukemia homeobox (PBX) transcription factors are known to regulate organogenesis, but their molecular targets and function in midbrain dopaminergic neurons (mDAn) as well as their role in neurodegenerative diseases are unknown. Here, we show that PBX1 controls a novel transcriptional network required for mDAn specification and survival, which is sufficient to generate mDAn from human stem cells. Mechanistically, PBX1 plays a dual role in transcription by directly repressing or activating genes, such as Onecut2 to inhibit lateral fates during embryogenesis, Pitx3 to promote mDAn development, and Nfe2l1 to protect from oxidative stress. Notably, PBX1 and NFE2L1 levels are severely reduced in dopaminergic neurons of the substantia nigra of Parkinson's disease (PD) patients and decreased NFE2L1 levels increases damage by oxidative stress in human midbrain cells. Thus, our results reveal novel roles for PBX1 and its transcriptional network in mDAn development and PD, opening the door for new therapeutic interventions.

• Keywords
• ChIP‐Seq, dopamine, dopaminergic differentiation, mesencephalon, stem cells,
• MeSH
• Cell Differentiation * MeSH
• DNA-Binding Proteins metabolism   MeSH
• Dopaminergic Neurons physiology   MeSH
• Gene Regulatory Networks * MeSH
• Humans MeSH
• Parkinson Disease pathology   MeSH
• Pre-B-Cell Leukemia Transcription Factor 1 MeSH
• Proto-Oncogene Proteins metabolism   MeSH
• Substantia Nigra pathology   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH
• Names of Substances
• DNA-Binding Proteins MeSH
• PBX1 protein, human MeSH Browser
• Pre-B-Cell Leukemia Transcription Factor 1 MeSH
• Proto-Oncogene Proteins MeSH

Tick-borne encephalitis virus (TBEV), the most medically relevant tick-transmitted flavivirus in Eurasia, targets the host central nervous system and frequently causes severe encephalitis. The severity of TBEV-induced neuropathogenesis is highly cell-type specific and the exact mechanism responsible for such differences has not been fully described yet. Thus, we performed a comprehensive analysis of alterations in host poly-(A)/miRNA/lncRNA expression upon TBEV infection in vitro in human primary neurons (high cytopathic effect) and astrocytes (low cytopathic effect). Infection with severe but not mild TBEV strain resulted in a high neuronal death rate. In comparison, infection with either of TBEV strains in human astrocytes did not. Differential expression and splicing analyses with an in silico prediction of miRNA/mRNA/lncRNA/vd-sRNA networks found significant changes in inflammatory and immune response pathways, nervous system development and regulation of mitosis in TBEV Hypr-infected neurons. Candidate mechanisms responsible for the aforementioned phenomena include specific regulation of host mRNA levels via differentially expressed miRNAs/lncRNAs or vd-sRNAs mimicking endogenous miRNAs and virus-driven modulation of host pre-mRNA splicing. We suggest that these factors are responsible for the observed differences in the virulence manifestation of both TBEV strains in different cell lines. This work brings the first complex overview of alterations in the transcriptome of human astrocytes and neurons during the infection by two TBEV strains of different virulence. The resulting data could serve as a starting point for further studies dealing with the mechanism of TBEV-host interactions and the related processes of TBEV pathogenesis.

• Keywords
• A3SS, alternative 3′ splice site, A5SS, alternative 5′ splice site, ACACA, Acetyl-CoA Carboxylase Alpha, AKR1C2, Aldo-Keto Reductase Family 1 Member C2, ANKS1A, Ankyrin Repeat And Sterile Alpha Motif Domain Containing 1A, ANOS1, Anosmin 1, AOX1, Aldehyde Oxidase 1, APOBEC3G, Apolipoprotein B MRNA Editing Enzyme Catalytic Subunit 3G, APOL1/6, Apolipoprotein L1/6, ARID2, AT-Rich Interaction Domain 2, AUTS2, Activator Of Transcription And Developmental Regulator AUTS2, Alternative splicing, Astrocytes, BCL11B, BAF Chromatin Remodeling Complex Subunit BCL11B, BCL9L, BCL9 Transcription Coactivator-like, BDKRB2, Bradykinin Receptor B2, BDNF, Brain Derived Neurotrophic Factor, BEND3, BEN Domain Containing 3, BSA, bovine serum albumin, BST2, Bone Marrow Stromal Cell Antigen 2, CALB1, Calbindin 1, CAMK2A, Calcium/Calmodulin Dependent Protein Kinase II Alpha, CD, complement determinant, CDKN1C, Cyclin Dependent Kinase Inhibitor 1C, CFAP61, Cilia And Flagella Associated Protein 61, CHRNA3, Cholinergic Receptor Nicotinic Alpha 3 Subunit, CHRNB4, Cholinergic Receptor Nicotinic Beta 4 Subunit, CLIC5, Chloride Intracellular Channel 5, CMPK2, Cytidine/Uridine Monophosphate Kinase 2, CNS, central nervous system, CNTN2, Contactin 2, CREG2, Cellular Repressor Of E1A Stimulated Genes 2, CXADR, Coxsackievirus B-Adenovirus Receptor, CYYR1, Cysteine And Tyrosine Rich 1, DACH1, Dachshund Family Transcription Factor 1, DAPI, diamidino-2-phenylindole, DCC, Netrin 1 Receptor, DCX, Doublecortin, DDX60, DExD/H-Box Helicase 60, DDX60L, DExD/H-Box 60 Like, DE, differentially expressed, DENV, Dengue virus, DIRAS2, DIRAS Family GTPase 2, DLX1/5/6, Distal-Less Homeobox 1/5/6, DNMT3B, DNA Methyltransferase 3 Beta, DPYSL2, Dihydropyrimidinase Like 2, EBF1, EBF Transcription Factor 1, EGF, Epidermal Growth Factor, ELAVL2/4, ELAV Like RNA Binding Protein 2/4, EPHB1, EPH Receptor B1, EPSTI1, Epithelial Stromal Interaction 1, ERBB4, Erb-B2 Receptor Tyrosine Kinase 4, ES, exon skipping, ESRRG, Estrogen Related Receptor Gamma, FGFb, Fibroblast Growth Factor 2, FPKM, Fragments Per Kilobase of transcript per Million mapped reads, FUT9, Fucosyltransferase 9, G2E3, G2/M−Phase Specific E3 Ubiquitin Protein Ligase, GABRG2, Gamma-Aminobutyric Acid Type A Receptor Subunit Gamma 2, GAPDH, Glyceraldehyde-3-Phosphate Dehydrogenase, GAS2L3, Growth Arrest Specific 2 Like 3, GAS7, Growth Arrest Specific 7, GATAD2B, GATA Zinc Finger Domain Containing 2B, GFAP, Glial Fibrillary Acidic Protein, GIPC2, GIPC PDZ Domain Containing Family Member 2, GLRA2, Glycine Receptor Alpha 2, GNG2, G Protein Subunit Gamma 2, GO, gene ontology, GOLGA4, Golgin A4, GRIN2A, Glutamate Ionotropic Receptor NMDA Type Subunit 2A, GSEA, gene set enrichment analysis, HERC5/6, HECT And RLD Domain Containing E3 Ubiquitin Protein Ligase 5/6, HEYL, Hes Related Family BHLH Transcription Factor With YRPW Motif Like, HPRT1, Hypoxanthine Phosphoribosyltransferase 1, HS, hot-spot, HSPA6, Heat Shock Protein Family A (Hsp70) Member 6, HUDD (ELAV4), Hu-Antigen D/ELAV Like Neuron-Specific RNA Binding Protein 4, IFI6, Interferon Alpha Inducible Protein 6, IFIH1 (MDA5), Interferon Induced With Helicase C Domain 1/Melanoma Differentiation-Associated Protein 5, IFIT1-3, Interferon Induced Protein With Tetratricopeptide Repeats 1–3, IFITM1/2, Interferon Induced Transmembrane Protein 1/2, IFN, interferon, IGB, Integrated Genome Browser, IL6, Interleukin 6, IR, intron retention, ISG20, Interferon Stimulated Exonuclease Gene 20, ISGF3, Interferon-Stimulated Gene Factor 3 Gamma, ISGs, interferon-stimulated genes, JEV, Japanese encephalitis virus, KCND2, Potassium Voltage-Gated Channel Subfamily D Member 2, KCNK10, Potassium Two Pore Domain Channel Subfamily K Member 10, KCNS2, Potassium Voltage-Gated Channel Modifier Subfamily S Member 2, KIT, KIT Proto-Oncogene, Receptor Tyrosine Kinase, KLHDC8A, Kelch Domain Containing 8A, KLHL13, Kelch Like Family Member 13, KRR1, KRR1 Small Subunit Processome Component Homolog, LCOR, Ligand Dependent Nuclear Receptor Corepressor, LEKR1, Leucine, Glutamate And Lysine Rich 1, LGI1, Leucine Rich Glioma Inactivated 1, LRRTM3, Leucine Rich Repeat Transmembrane Neuronal 3, LSV, local splicing variation, LUZP2, Leucine Zipper Protein 2, MAN1A1, Mannosidase Alpha Class 1A Member 1, MAP2, Microtubule Associated Protein 2, MBNL2, Muscleblind Like Splicing Regulator 2, MCTP1, Multiple C2 And Transmembrane Domain Containing 1, MMP13, Matrix Metallopeptidase 13, MN1, MN1 Proto-Oncogene, Transcriptional Regulator, MOI, multiplicity of infection, MTUS2, Microtubule Associated Scaffold Protein 2, MX2, MX Dynamin Like GTPase 2, MYCN, MYCN Proto-Oncogene, BHLH Transcription Factor, NAV1, Neuron Navigator 1, NCAM1, Neural Cell Adhesion Molecule 1, NDRG4, N-Myc Downstream-Regulated Gene 4 Protein, NEK7, NIMA Related Kinase 7, NFASC, Neurofascin, NKAIN1, Sodium/Potassium Transporting ATPase Interacting 1, NMI, N-Myc And STAT Interactor 2, NRAP, Nebulin Related Anchoring Protein, NRARP, NOTCH Regulated Ankyrin Repeat Protein, NREP, Neuronal Regeneration Related Protein, NRN1, Neuritin 1, NS3, flaviviral non-structural protein 3, NXPH2, Neurexophilin 2, NYNRIN, NYN Domain And Retroviral Integrase Containing, Neurons, Neuropathogenesis, OAS, 2′-5′-Oligoadenylate Synthetase, OASL, 2′-5′-Oligoadenylate Synthetase Like, ONECUT2, ONECUT-2 Homeodomain Transcription Factor, OPCML, Opioid Binding Protein/Cell Adhesion Molecule Like, OTX2, Orthodenticle Homeobox 2, PBS, phosphate buffer saline, PBX1, Pre-B-Cell Leukemia Transcription Factor 1, PCDH18/20, Protocadherin 18/20, PFKFB3, 6-Phosphofructo-2-Kinase/Fructose-2,6-Biphosphatase 3, PIK3C2B, Phosphatidylinositol-4-Phosphate 3-Kinase Catalytic Subunit Type 2 Beta, PIP4P2, Phosphatidylinositol-4,5-Bisphosphate 4-Phosphatase 2, PLCH1, Phospholipase C Eta 1, POU3F4, Brain-Specific Homeobox/POU Domain Protein 4, PPM1L, Protein Phosphatase, Mg2+/Mn2+ Dependent 1L, PPP1R17, Protein Phosphatase 1 Regulatory Subunit 17, PRDM12, PR Domain Zinc Finger Protein 12, PSI, percent selective index, PSRC1, Proline And Serine Rich Coiled-Coil 1, PTPN5, Protein Tyrosine Phosphatase Non-Receptor Type 5, PTPRH, Protein Tyrosine Phosphatase Receptor Type H, RAPGEF5, Rap Guanine Nucleotide Exchange Factor 5, RBFOX1, RNA Binding Fox-1 Homolog 1, RIG-I (DDX58), Retinoic Acid-Inducible Gene 1 Protein, RNF212, Ring Finger Protein 212, RNVU1, RNA, Variant U1 Small Nuclear, RSAD2, Radical S-Adenosyl Methionine Domain Containing 2, RTL8B, Retrotransposon Gag Like 8B, Response to infection, SAMD9, Sterile Alpha Motif Domain Containing 9, SEMA3E, Semaphorin 3E, SH3TC2, SH3 Domain And Tetratricopeptide Repeats 2, SHF, Src Homology 2 Domain Containing F, SHISAL1, Shisa Like 1, SIAH3, Siah E3 Ubiquitin Protein Ligase Family Member 3, SIRPA, Signal Regulatory Protein Alpha, SLITRK5, SLIT And NTRK Like Family Member 5, SNP, single-nucleotide polymorphism, SOGA1, Suppressor Of Glucose, Autophagy Associated 1, SPSB4, SplA/Ryanodine Receptor Domain And SOCS Box Containing 4, ST6GAL1, ST6 Beta-Galactoside Alpha-2,6-Sialyltransferase 1, TBC1D30, TBC1 Domain Family Member 30, TBEV, Tick-borne encephalitis virus, TFAP2A, Transcription Factor AP-2 Alpha, TFAP2B, Transcription Factor AP-2 Beta, THSD7A, Thrombospondin Type 1 Domain Containing 7A, THUMPD2, THUMP Domain-Containing Protein 2/SAM-Dependent Methyltransferase, TIPARP, TCDD Inducible Poly(ADP-Ribose) Polymerase, TM4SF18, Transmembrane 4 L Six Family Member 18, TMC8, Transmembrane Channel Like 6, TMEM229B, Transmembrane Protein 229B, TMTC1, Transmembrane O-Mannosyltransferase Targeting Cadherins 1, TNFSF10, TNF Superfamily Member 10, TRHDE, Thyrotropin Releasing Hormone Degrading Enzyme, TRIM38, Tripartite Motif Containing 38, TSHZ1, Teashirt Zinc Finger Homeobox 1, Tick-borne encephalitis virus, Transcriptomics, USP18, Ubiquitin Specific Peptidase 18/ISG15-Specific-Processing Protease, UTR, untranslated region, UTS2R, Urotensin 2 Receptor, WNV, West Nile virus, XAF1, XIAP Associated Factor 1, XRN1, 5′-3′ Exoribonuclease 1, ZIKV, Zika virus, ZMAT3, Zinc Finger Matrin-Type 3, ZMYM5, Zinc Finger MYM-Type Containing 5, ZNF124, Zinc Finger Protein 124, ZNF730, Zinc Finger Protein 730, gRNA, genomic TBEV RNA, hNSC, human neural stem cells, lncRNA, long non-coding RNA, mRNA, messenger RNA, miRNA, miRNA, micro RNA, ncRNA, non-coding RNA, pc-mRNA, protein-coding mRNA, qRT-PCR, quantitative reverse transcription real-time PCR, snRNP, small nuclear ribonucleoproteins, vd-sRNA, virus-derived small RNA,
• Publication type
• Journal Article MeSH