Formation and specification of distal leg segments in Drosophila by dual Bar homeobox genes, BarH1 and BarH2

Development ◽  
2000 ◽  
Vol 127 (4) ◽  
pp. 769-778 ◽  
Author(s):  
T. Kojima ◽  
M. Sato ◽  
K. Saigo
Keyword(s):  
Homeobox Genes ◽  
Homeobox Gene ◽  
Boundary Formation ◽  
Tarsal Segment ◽  
Fas Ii ◽  
Antagonistic Interactions

Here, we show that BarH1 and BarH2, a pair of Bar homeobox genes, play essential roles in the formation and specification of the distal leg segments of Drosophila. In early third instar, juxtaposition of Bar-positive and Bar-negative tissues causes central folding that may separate future tarsal segments 2 from 3, while juxtaposition of tissues differentially expressing Bar homeobox genes at later stages gives rise to segmental boundaries of distal tarsi including the tarsus/pretarsus boundary. Tarsus/pretarsus boundary formation requires at least two different Bar functions, early antagonistic interactions with a pretarsus-specific homeobox gene, aristaless, and the subsequent induction of Fas II expression in pretarsus cells abutting tarsal segment 5. Bar homeobox genes are also required for specification of distal tarsi. Bar expression requires Distal-less but not dachshund, while early circular dachshund expression is delimited interiorly by BarH1 and BarH2.

Requirements of Lim1, a Drosophila LIM-homeobox gene, for normal leg and antennal development

Development ◽  
2000 ◽  
Vol 127 (20) ◽  
pp. 4315-4323 ◽  
Author(s):  
T. Tsuji ◽  
A. Sato ◽  
I. Hiratani ◽  
M. Taira ◽  
K. Saigo ◽  
...  
Keyword(s):  
Ectopic Expression ◽  
Homeobox Genes ◽  
Homeobox Gene ◽  
Homeodomain Protein ◽  
Border Cells ◽  
Null Mutant ◽  
Tarsal Segment ◽  
Segment Boundary ◽  
Leg Development ◽  
Antagonistic Interactions

During Drosophila leg development, the distal-most compartment (pretarsus) and its immediate neighbour (tarsal segment 5) are specified by a pretarsus-specific homeobox gene, aristaless, and tarsal-segment-specific Bar homeobox genes, respectively; the pretarsus/tarsal-segment boundary is formed by antagonistic interactions between Bar and pretarsus-specific genes that include aristaless (Kojima, T., Sato, M. and Saigo, K. (2000) Development 127, 769–778). Here, we show that Drosophila Lim1, a homologue of vertebrate Lim1 encoding a LIM-homeodomain protein, is involved in pretarsus specification and boundary formation through its activation of aristaless. Ectopic expression of Lim1 caused aristaless misexpression, while aristaless expression was significantly reduced in Lim1-null mutant clones. Pretarsus Lim1 expression was negatively regulated by Bar and abolished in leg discs lacking aristaless activity, which was associated with strong Bar misexpression in the presumptive pretarsus. No Lim1 misexpression occurred upon aristaless misexpression. The concerted function of Lim1 and aristaless was required to maintain Fasciclin 2 expression in border cells and form a smooth pretarsus/tarsal-segment boundary. Lim1 was also required for femur, coxa and antennal development.

Nkx-2.5: a novel murine homeobox gene expressed in early heart progenitor cells and their myogenic descendants

Development ◽  
1993 ◽  
Vol 119 (2) ◽  
pp. 419-431 ◽  
Author(s):  
T.J. Lints ◽  
L.M. Parsons ◽  
L. Hartley ◽  
I. Lyons ◽  
R.P. Harvey
Keyword(s):  
Progenitor Cells ◽  
Myogenic Differentiation ◽  
Homeobox Genes ◽  
Homeobox Gene ◽  
Heart Tube ◽  
New Members ◽  
Mesoderm Development ◽  
Early Entry ◽  
Developing Heart ◽  
Valuable Marker

We have isolated two murine homeobox genes, Nkx-2.5 and Nkx-2.6, that are new members of a sp sub-family of homeobox genes related to Drosophila NK2, NK3 and NK4/msh-2. In this paper, we focus on the Nkx-2.5 gene and its expression pattern during post-implantation development. Nkx-2.5 transcripts are first detected at early headfold stages in myocardiogenic progenitor cells. Expression preceeds the onset of myogenic differentiation, and continues in cardiomyocytes of embryonic, foetal and adult hearts. Transcripts are also detected in future pharyngeal endoderm, the tissue believed to produce the heart inducer. Expression in endoderm is only found laterally, where it is in direct apposition to promyocardium, suggesting an interaction between the two tissues. After foregut closure, Nkx-2.5 expression in endoderm is limited to the pharyngeal floor, dorsal to the developing heart tube. The thyroid primordium, a derivative of the pharyngeal floor, continues to express Nkx-2.5 after transcript levels diminish in the rest of the pharynx. Nkx-2.5 transcripts are also detected in lingual muscle, spleen and stomach. The expression data implicate Nkx-2.5 in commitment to and/or differentiation of the myocardial lineage. The data further demonstrate that cardiogenic progenitors can be distinguished at a molecular level by late gastrulation. Nkx-2.5 expression will therefore be a valuable marker in the analysis of mesoderm development and an early entry point for dissection of the molecular basis of myogenesis in the heart.

The Caenorhabditis elegans lim-6 LIM homeobox gene regulates neurite outgrowth and function of particular GABAergic neurons

Development ◽  
1999 ◽  
Vol 126 (7) ◽  
pp. 1547-1562 ◽  
Author(s):  
O. Hobert ◽  
K. Tessmar ◽  
G. Ruvkun
Keyword(s):  
Epithelial Cells ◽  
Homeobox Genes ◽  
Homeobox Gene ◽  
Acid Decarboxylase ◽  
Neural Function ◽  
C Elegans ◽  
Gaba Synthesis ◽  
And Function ◽  
Rate Limiting ◽  
Enteric Muscle

We describe here the functional analysis of the C. elegans LIM homeobox gene lim-6, the ortholog of the mammalian Lmx-1a and b genes that regulate limb, CNS, kidney and eye development. lim-6 is expressed in a small number of sensory-, inter- and motorneurons, in epithelial cells of the uterus and in the excretory system. Loss of lim-6 function affects late events in the differentiation of two classes of GABAergic motorneurons which control rhythmic enteric muscle contraction. lim-6 is required to specify the correct axon morphology of these neurons and also regulates expression of glutamic acid decarboxylase, the rate limiting enzyme of GABA synthesis in these neurons. Moreover, lim-6 gene activity and GABA signaling regulate neuroendocrine outputs of the nervous system. In the chemosensory system lim-6 regulates the asymmetric expression of a probable chemosensory receptor. lim-6 is also required in epithelial cells for uterine morphogenesis. We compare the function of lim-6 to those of other LIM homeobox genes in C. elegans and suggest that LIM homeobox genes share the common theme of controlling terminal neural differentiation steps that when disrupted lead to specific neuroanatomical and neural function defects.

Regulation of ectodermal and excretory function by the C. elegans POU homeobox gene ceh-6

Development ◽  
2001 ◽  
Vol 128 (5) ◽  
pp. 779-790 ◽  
Author(s):  
T.R. Burglin ◽  
G. Ruvkun
Keyword(s):  
Transcription Factor ◽  
Epithelial Cells ◽  
Homeobox Genes ◽  
Homeobox Gene ◽  
Null Mutant ◽  
Reporter Construct ◽  
Excretory Function ◽  
C Elegans ◽  
Gfp Reporter ◽  
Excretory Cell

Caenorhabditis elegans has three POU homeobox genes, unc-86, ceh-6 and ceh-18. ceh-6 is the ortholog of vertebrate Brn1, Brn2, SCIP/Oct6 and Brn4 and fly Cf1a/drifter/ventral veinless. Comparison of C. elegans and C. briggsae CEH-6 shows that it is highly conserved. C. elegans has only three POU homeobox genes, while Drosophila has five that fall into four families. Immunofluorescent detection of the CEH-6 protein reveals that it is expressed in particular head and ventral cord neurons, as well as in rectal epithelial cells, and in the excretory cell, which is required for osmoregulation. A deletion of the ceh-6 locus causes 80% embryonic lethality. During morphogenesis, embryos extrude cells in the rectal region of the tail or rupture, indicative of a defect in the rectal epithelial cells that express ceh-6. Those embryos that hatch are sick and develop vacuoles, a phenotype similar to that caused by laser ablation of the excretory cell. A GFP reporter construct expressed in the excretory cell reveals inappropriate canal structures in the ceh-6 null mutant. Members of the POU-III family are expressed in tissues involved in osmoregulation and secretion in a number of species. We propose that one evolutionary conserved function of the POU-III transcription factor class could be the regulation of genes that mediate secretion/osmoregulation.

Comprehensive Analysis of Homeobox Gene Expression in Hodgkin Lymphoma Cell Lines Reveals Similarities to Prostate Carcinoma.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 966-966
Author(s):  
Stefan Nagel ◽  
Christof Burek ◽  
Hilmar Quentmeier ◽  
Corinna Meyer ◽  
Andreas Rosenwald ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
B Cell ◽  
Hodgkin Lymphoma ◽  
Cell Lines ◽  
Prostate Carcinoma ◽  
Homeobox Genes ◽  
Homeobox Gene ◽  
Cell Cycle Regulators ◽  
Rt Pcr

Abstract Homeobox genes code for transcription factors with essential regulatory impact on cellular processes during embryogenesis and in the adult. Increasingly, members of the circa 200 gene strong family are emerging as major oncogenic players, prompting our investigation into possible homeobox gene dysregulation in Hodgkin lymphoma (HL) in which no recurrent oncogene involvement has been known. Accordingly, we screened 6 well characterized HL cell lines (HDLM-2, KM-H2, L-1236, L-428, L-540, SUP-HD1) and 3 non-Hodgkin lymphoma (NHL) cell lines (RC-K8, RI-1, SC-1) for homeobox gene expression using Affymetrix U133-2.0 whole-genome oligonucleotide microarrays. Of 15 candidate genes thus shown to reveal HL-specific expression patterns, 5 homeobox genes were shortlisted as potentially key dysregulatory targets in HL after additional RT-PCR expression analysis relative to controls. While 3/5 homeobox genes were upregulated in HL (HOXB9, HOXC8, HLXB9), 2/5 were downregulated (BOB1, PAX5). Furthermore, cloning and sequencing RT-PCR products obtained with degenerate primers recognizing conserved homeobox motifs confirmed the predominant expression of HOXB9 in HL cells. However, fluorescence in situ hybridization (FISH) analysis of the HOXB locus (at 17q21) revealed no cytogenetic aberrations, indicating that its activation is conducted non-chromosomally in HL cells. Surprisingly, known target genes of HOXB9 and HOXC8 remained unperturbed, implying novel downstream effector pathways in HL cells. Antisense oligos directed against HOXB9 and forced expression experiments using cloned full length HOXB9 cDNA indicated its involvement in both proliferation and apoptosis. Cell cycle regulators BTG1, BTG2 and GEMININ have been described to interact with HOXB9 and may represent potential targets deserving investigation. We recently showed that HLXB9 promotes IL6 expression in HL cells in response to a constitutively active PI3K signalling pathway therein (Nagel et al., Leukemia19, 841–6, 2005). Our most recent data indicate that HLXB9 is also expressed in various NHL cell lines including anaplastic, diffuse and mediastinal large cell as well as follicular B-cell lymphomas while expression is notably absent from Burkitt, mantle cell and natural killer T-cell lymphomas reflecting their pathologic classification. Intriguingly, our data highlight unexpected similarities between HL and prostate cancer cells which together uniquely overexpress HOXB9, HOXC8 and HLXB9 (or its close homolog GBX2). Additional genes expressed in prostate carcinoma (HOXB13, PRAC1, PRAC2) were detected in two HL cell lines (KM-H2 and L-428) suggesting further parallels may be revealed. Detection of downregulated B-cell differentiation factors BOB1 and PAX5 in our panel of HL cell lines validated this approach. Both factors were previously implicated in oncogenesis of HL lacking IGH rearrangements and other key B-cell characteristics. In summary, we identified a unique homeobox gene expression pattern involving HOXB9, HOXB13, HOXC8 and HLXB9 in HL cell lines resembling that of prostate carcinoma cells. Overexpressed HOXB9 contributes to proliferation and protects against apoptosis in HL cells potentially via interacting with cell cycle regulators BTG1/2 and/or GEMININ.

Inhibition of TLX3 and NKX2-5 in t(5;14)(q35;q32) T-ALL after Blocking Remote 3′-BCL11B Enhancer Sequences with Matching DNA Oligos Reveals Coregulation by PU.1 and HMGA1.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2212-2212
Author(s):  
Stefan Nagel ◽  
Michaela Scherr ◽  
Alexander Kel ◽  
Klaus Hornischer ◽  
Gregory E. Crawford ◽  
...  
Keyword(s):  
T Cell ◽  
Nuclear Matrix ◽  
Gene Activation ◽  
Regulatory Region ◽  
Homeobox Genes ◽  
Homeobox Gene ◽  
Genomic Analysis ◽  
Regulatory Sequences ◽  
Promoter Regions ◽  
Gene Dysregulation

Abstract In T-cell acute lymphoblastic leukaemia (T-ALL) alternative t(5;14)(q35;q32.2) forms effect leukemic dysregulation of either TLX3 or NKX2-5 homeobox genes at 5q35 by juxtaposition with 3′-BCL11B at 14q32.2. Putative regulatory sequences underlying ectopic homeobox gene activation in t(5;14), and their mode of action have remained poorly understood mainly because breakpoints at 14q32.2 are widely scattered over the ~1 Mbp genomic desert region. We pooled cytogenetic data from t(5;14) cell lines together with published clinical data to refine the BCL11B downstream breakpoint cluster region (bcr). Ectopic homeobox gene dysregulation was investigated by DNA-i(nhibitory-treatments) with 26-mer double-stranded DNA oligo(nucleotide)s directed against putative enhancers using NKX2-5 expression as endpoints. Enhancer targets were provisionally identified from orphan T-cell DNase-I hypersensive sites (DNaseI-HS) located between 3′-BCL11B and VRK1. NKX2-5 downregulation in t(5;14) PEER cells was almost entirely restricted to DNAi targeting enhancers within the distal bcr and was dose- and sequence-dependent. Interestingly, enhancers near 3′-BCL11B regulated that gene only. These data imply that enhancer-promoter distances and/or locations are important for long-range gene regulation. Chromatin immunoprecipation assays showed that the four most effectual NKX2-5 ectopic enhancers were hyperacetylated. These enhancers clustered ~1 Mbp downstream of BCL11B, within a region displaying multiple regulatory stigmata, including a TCRA-enhancer motif, and abyssal sequence-conservation (“5-Way Regulatory Potential”). Paradoxically, although TLX3/NKX2-5 promoter/exon-1 regions were hypo-acetylated, their expression decreased after TSA treatment, implying extrinsic regulation by factor(s) subject to acetylation-control. PU.1 is known to get transcriptionally repressed by TSA and potentially binds TLX3/NKX2-5 upstream promoter regions. Knockdown of PU.1 effected downregulation of both homeobox genes. Moreover, genomic analysis showed preferential enrichment near validated ectopic enhancers of binding sites for the PU.1-cofactor HMGA1, knockdown of which also inhibited NKX2-5 in PEER cells. Analysis of nuclear matrix attachment (NMA) in PEER cells showed enhanced attachment near to the most effectual enhancer cluster which was alleviated by TSA-treatment. Interestingly, the juxtapositional genomic regions of “active” ins(14;5) rearrangements driving NKX2-5 expression exhibited tight NMA, forming structures reminiscent of “active chromatin hubs”. These findings lead us to propose that HMGA1 and PU.1 co-regulate ectopic homeobox gene expression in t(5;14) T-ALL by interactions mediated at the nuclear matrix, possibly mediated by SATB1 binding. Our data document homeobox gene dysregulation by a novel regulatory region at 3′-BCL11B responsive to HDAC-inhibition and highlight a novel class of potential therapeutic target amid “junk” DNA.

A HoxD11 Homeobox Gene Mutation Associated With Congenital Absent Radius But Without The Thrombocytopenia Of The TAR Syndrome Or a HoxA11 Mutation

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4837-4837
Author(s):  
Roger A. Fleischman
Keyword(s):  
Potential Role ◽  
Conflicts Of Interest ◽  
Homeobox Genes ◽  
Homeobox Gene ◽  
Incomplete Penetrance ◽  
Potential Candidate ◽  
Negative Finding ◽  
Tar Syndrome ◽  
Absent Radius

HoxA11 and HoxD11 are homeobox genes critical for normal development of the forearm and thus are potential candidate genes for involvement in the pathogenesis of the thrombocytopenia/absent radius (TAR) syndrome. However, we previously reported an absence of coding sequence mutations in either HoxA11 or HoxD11 in a series of 10 unrelated TAR syndrome patients (Fleischman RA et al., Br J Haematol., 116:367-75, 2002). Despite this negative finding, interest in the potential role of homeobox genes in the TAR syndrome has been supported by a report of a HoxA11 mutation occurring in two kindreds with amegakaryocytic thrombocytopenia and radio-ulnar synostosis, a less pronounced more proximal pattern of radial malformation (Thompson AA and Nguyen LT. Nat Genet., 26:397-8, 2000). Unlike HoxA11, however, no mutations in the human HoxD11 gene have been described thus far that would help elucidate the potential role of this paralogous gene in megakaryopoiesis or the TAR syndrome. We now describe a novel mutation in human HoxD11 that results in a polyalanine sequence expansion, (GCG)6→ (GCG)8, and report that this mutation is associated with a unilateral absent radius in the affected propositus. A familial syndrome is suggested in this kindred, moreover, by the prior observation of a bilateral absent radius in a deceased maternal aunt. This mutation was not present in more than 100 unrelated normal subjects or 8 other unrelated individuals with sporadic absence of the radius. Two other living maternal relatives also carried the mutation but did not exhibit any radial defects, a finding consistent with autosomal dominance with incomplete penetrance, an inheritance pattern reported for short polyalanine expansion mutations in the related homeobox gene HoxD13 which cause synpolydactyly. In contrast to the reported HoxA11 mutation, however, neither the propositus nor the mutation carriers of this HoxD11 mutation exhibited thrombocytopenia or any other cytopenias or congenital defect. The results suggest that at least one class of mutation in human HoxD11 may be sufficient to cause an absent radius syndrome but unlike the reported HoxA11 mutation, does not adversely affect megakaryopoiesis. The findings further suggest that additional studies of the TAR syndrome may be necessary to exclude as yet undetected non-coding mutations in promoter or enhancer sequences that alter the expression of HoxA11, HoxD11 or other homeobox genes critical for radial development and/or megakaryopoiesis. This work was supported by a VA Merit Award. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Erythroid-restricted expression of homeobox genes of the human HOX 2 locus

Blood ◽  
1991 ◽  
Vol 78 (9) ◽  
pp. 2248-2252 ◽  
Author(s):  
CH Mathews ◽  
K Detmer ◽  
E Boncinelli ◽  
HJ Lawrence ◽  
C Largman
Keyword(s):  
Cell Lines ◽  
Expression Patterns ◽  
Homeobox Genes ◽  
Homeobox Gene ◽  
Leukemic Cell ◽  
Hematopoietic Cell ◽  
Erythroid Cell ◽  
Small Series ◽  
Hematopoietic Cell Lines ◽  
In Cells

We have previously reported that certain members of the HOX 1 and HOX 2 clusters of class 1 homeobox-containing genes showed lineage-restricted patterns of expression in a small series of human hematopoietic cell lines. We now report on the expression patterns of the entire HOX 2 cluster, consisting of nine homeobox genes, in a broad survey of leukemic cell lines of different phenotypes. The most striking observation is that all but one of the HOX 2 genes are consistently expressed in cells with erythroid character and/or potential, but, with rare exception, not in cells with myelomonocytic or T- or B-lymphoid phenotype. By contrast, several genes of the HOX 1 and 3 loci are not expressed in erythroid lines. Within erythroid cell lines, many of the HOX 2 genes are expressed as multiple transcripts. Expression of some HOX 2 genes is detectable in normal human marrow. These data show that in human hematopoietic cell lines HOX 2 homeobox gene expression is largely restricted to cells of erythroid phenotype and suggest that these genes play a role in erythropoiesis.

scholarly journals Identification of a Prognostic Signature Associated With the Homeobox Gene Family for Bladder Cancer

2021 ◽  
Vol 8 ◽  
Author(s):  
Bingqi Dong ◽  
Jiaming Liang ◽  
Ding Li ◽  
Wenping Song ◽  
Jinbo Song ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
High Risk ◽  
Gene Family ◽  
Risk Score ◽  
Risk Group ◽  
Homeobox Genes ◽  
Homeobox Gene ◽  
High Risk Group ◽  
Low Risk ◽  
Prognostic Signature

Background: Bladder cancer (BLCA) is a common malignant tumor of the genitourinary system, and there is a lack of specific, reliable, and non-invasive tumor biomarker tests for diagnosis and prognosis evaluation. Homeobox genes play a vital role in BLCA tumorigenesis and development, but few studies have focused on the prognostic value of homeobox genes in BLCA. In this study, we aim to develop a prognostic signature associated with the homeobox gene family for BLCA.Methods: The RNA sequencing data, clinical data, and probe annotation files of BLCA patients were downloaded from the Gene Expression Omnibus database and the University of California, Santa Cruz (UCSC), Xena Browser. First, differentially expressed homeobox gene screening between tumor and normal samples was performed using the “limma” and robust rank aggregation (RRA) methods. The mutation data were obtained with the “TCGAmutation” package and visualized with the “maftools” package. Kaplan–Meier curves were plotted with the “survminer” package. Then, a signature was constructed by logistic regression analysis. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed using “clusterProfiler.” Furthermore, the infiltration level of each immune cell type was estimated using the single-sample gene set enrichment analysis (ssGSEA) algorithm. Finally, the performance of the signature was evaluated by receiver-operating characteristic (ROC) curve and calibration curve analyses.Results: Six genes were selected to construct this prognostic model: TSHZ3, ZFHX4, ZEB2, MEIS1, ISL1, and HOXC4. We divided the BLCA cohort into high- and low-risk groups based on the median risk score calculated with the novel signature. The overall survival (OS) rate of the high-risk group was significantly lower than that of the low-risk group. The infiltration levels of almost all immune cells were significantly higher in the high-risk group than in the low-risk group. The average risk score for the group that responded to immunotherapy was significantly lower than that of the group that did not.Conclusion: We constructed a risk prediction signature with six homeobox genes, which showed good accuracy and consistency in predicting the patient’s prognosis and response to immunotherapy. Therefore, this signature can be a potential biomarker and treatment target for BLCA patients.

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