Multiple Roles and Interactions of Tbx4 and Tbx5 in Development of the Respiratory System
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{"title"=>"Multiple Roles and Interactions of Tbx4 and Tbx5 in Development of the Respiratory System", "type"=>"journal", "authors"=>[{"first_name"=>"Ripla", "last_name"=>"Arora", "scopus_author_id"=>"53163349600"}, {"first_name"=>"Ross J.", "last_name"=>"Metzger", "scopus_author_id"=>"7102961726"}, {"first_name"=>"Virginia E.", "last_name"=>"Papaioannou", "scopus_author_id"=>"7005898389"}], "year"=>2012, "source"=>"PLoS Genetics", "identifiers"=>{"scopus"=>"2-s2.0-84866174979", "sgr"=>"84866174979", "issn"=>"15537390", "doi"=>"10.1371/journal.pgen.1002866", "pmid"=>"22876201", "isbn"=>"1553-7404 (Electronic)\\r1553-7390 (Linking)", "pui"=>"365631232"}, "id"=>"58b135eb-4acd-3dbc-a322-086e61138f16", "abstract"=>"Normal development of the respiratory system is essential for survival and is regulated by multiple genes and signaling pathways. Both Tbx4 and Tbx5 are expressed throughout the mesenchyme of the developing lung and trachea; and, although multiple genes are known to be required in the epithelium, only Fgfs have been well studied in the mesenchyme. In this study, we investigated the roles of Tbx4 and Tbx5 in lung and trachea development using conditional mutant alleles and two different Cre recombinase transgenic lines. Loss of Tbx5 leads to a unilateral loss of lung bud specification and absence of tracheal specification in organ culture. Mutants deficient in Tbx4 and Tbx5 show severely reduced lung branching at mid-gestation. Concordant with this defect, the expression of mesenchymal markers Wnt2 and Fgf10, as well as Fgf10 target genes Bmp4 and Spry2, in the epithelium is downregulated. Lung branching undergoes arrest ex vivo when Tbx4 and Tbx5 are both completely lacking. Lung-specific Tbx4 heterozygous;Tbx5 conditional null mice die soon after birth due to respiratory distress. These pups have small lungs and show severe disruptions in tracheal/bronchial cartilage rings. Sox9, a master regulator of cartilage formation, is expressed in the trachea; but mesenchymal cells fail to condense and consequently do not develop cartilage normally at birth. Tbx4;Tbx5 double heterozygous mutants show decreased lung branching and fewer tracheal cartilage rings, suggesting a genetic interaction. Finally, we show that Tbx4 and Tbx5 interact with Fgf10 during the process of lung growth and branching but not during tracheal/bronchial cartilage development.", "link"=>"http://www.mendeley.com/research/multiple-roles-interactions-tbx4-tbx5-development-respiratory-system", "reader_count"=>46, "reader_count_by_academic_status"=>{"Professor > Associate Professor"=>2, "Researcher"=>10, "Student > Ph. D. Student"=>8, "Student > Postgraduate"=>2, "Student > Master"=>9, "Other"=>4, "Student > Bachelor"=>4, "Lecturer > Senior Lecturer"=>2, "Professor"=>5}, "reader_count_by_user_role"=>{"Professor > Associate Professor"=>2, "Researcher"=>10, "Student > Ph. D. Student"=>8, "Student > Postgraduate"=>2, "Student > Master"=>9, "Other"=>4, "Student > Bachelor"=>4, "Lecturer > Senior Lecturer"=>2, "Professor"=>5}, "reader_count_by_subject_area"=>{"Engineering"=>2, "Biochemistry, Genetics and Molecular Biology"=>11, "Nursing and Health Professions"=>1, "Agricultural and Biological Sciences"=>22, "Medicine and Dentistry"=>7, "Veterinary Science and Veterinary Medicine"=>1, "Chemistry"=>1, "Immunology and Microbiology"=>1}, "reader_count_by_subdiscipline"=>{"Engineering"=>{"Engineering"=>2}, "Medicine and Dentistry"=>{"Medicine and Dentistry"=>7}, "Chemistry"=>{"Chemistry"=>1}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>22}, "Nursing and Health Professions"=>{"Nursing and Health Professions"=>1}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>11}, "Veterinary Science and Veterinary Medicine"=>{"Veterinary Science and Veterinary Medicine"=>1}}, "reader_count_by_country"=>{"United States"=>3, "South Africa"=>1}, "group_count"=>1}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/598137"], "description"=>"<p>(A–X) Marker analysis of control and <i>Tbx4</i>- and <i>Tbx5</i>-deficient lungs using whole mount ISH (A–O, S–X) and IHC (P–R): Fewer foci of <i>Fgf10</i> expression were seen in the <i>Tbx4</i> and <i>Tbx5</i>-deficient lungs (B,C) compared to control (A). cr, cranial; m, medial; cd, caudal; a, accesory lobes. Fgf10 target genes <i>Bmp4</i> (F,G,H) and <i>Spry2</i> (I,J) and canonical <i>Wnt2</i> (K,L,M) were downregulated in <i>Tbx4</i> and <i>Tbx5</i>-deficient lungs compared to controls. <i>Fgfr2</i> (D,E), <i>Etv5</i> (N,O), PECAM (P,Q,R), <i>Shh</i> (S,T), <i>Ptc</i> (U,V) and <i>Nkx2.1</i> (W,X) were expressed similarly in controls and <i>Tbx4</i> and <i>Tbx5</i>-deficient lungs.</p>", "links"=>[], "tags"=>["affects", "signaling", "pathway"], "article_id"=>268640, "categories"=>["Medicine", "Genetics", "Developmental Biology"], "users"=>["Ripla Arora", "Ross J. Metzger", "Virginia E. Papaioannou"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1002866.g005", "stats"=>{"downloads"=>2, "page_views"=>19, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Loss_of_Tbx4_and_Tbx5_affects_the_Fgf10_signaling_pathway_and_Wnt2_expression_/268640", "title"=>"Loss of <i>Tbx4</i> and <i>Tbx5</i> affects the <i>Fgf10</i> signaling pathway and <i>Wnt2</i> expression.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-08-02 02:24:00"}
  • {"files"=>["https://ndownloader.figshare.com/files/598649"], "description"=>"1<p><i>Tbx4<sup>−</sup></i> and <i>Tbx5<sup>−</sup></i> alleles are generated by recombination of the floxed alleles in the germ line due to germ line expression of the <i>Tbx4<sup>cre</sup></i> allele <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1002866#pgen.1002866-Naiche4\" target=\"_blank\">[38]</a>, <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1002866#pgen.1002866-Douglas1\" target=\"_blank\">[63]</a>.</p>", "links"=>[], "tags"=>["allelic", "combinations", "descriptive"], "article_id"=>269155, "categories"=>["Medicine", "Genetics", "Developmental Biology"], "users"=>["Ripla Arora", "Ross J. Metzger", "Virginia E. Papaioannou"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1002866.t001", "stats"=>{"downloads"=>1, "page_views"=>26, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Different_allelic_combinations_and_the_descriptive_nomenclature_/269155", "title"=>"Different allelic combinations and the descriptive nomenclature.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2012-08-02 02:32:35"}
  • {"files"=>["https://ndownloader.figshare.com/files/597666"], "description"=>"<p>(A–I) Foreguts were isolated between 8–16 somite stages and analyzed by ISH following culture. <i>Nkx2.1</i> (A), <i>Tbx4</i> (B) and <i>Tbx5</i> (C) expression in lung buds (arrows) and tracheal primordia (yellow arrowhead) was confirmed in control cultures. Excision of <i>Tbx5</i> using 4-OH tamoxifen in conditional null foreguts with <i>CreER</i> leads to the loss of <i>Nkx2.1</i> expression in one of the lung buds at 3 (E) or 4 days (H). Conditional double nulls (F,I) carrying <i>CreER</i> show a phenotype similar to the conditional <i>Tbx5</i> nulls, suggesting additional removal of <i>Tbx4</i> does not exacerbate the phenotype. <i>Nkx2.1</i> expression was absent in the foregut tube of conditional <i>Tbx5</i> null and conditional double null foreguts after 3 or 4 days of culture (yellow arrowheads in E,F,H,I) compared to controls (D,G). Conditional <i>Tbx5</i> nulls show reduced <i>Wnt2</i> expression (K) and absence of <i>Wnt2b</i> expression (M) in the developing lung buds as compared to controls (J,L). Black arrowheads (J) point to <i>Wnt2</i> expression in the heart in the controls. ht, heart; th, thyroid primordia.</p>", "links"=>[], "tags"=>["leads", "aberrant", "bud", "trachea"], "article_id"=>268164, "categories"=>["Medicine", "Genetics", "Developmental Biology"], "users"=>["Ripla Arora", "Ross J. Metzger", "Virginia E. Papaioannou"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1002866.g002", "stats"=>{"downloads"=>1, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Early_loss_of_Tbx5_leads_to_aberrant_lung_bud_and_trachea_specification_/268164", "title"=>"Early loss of <i>Tbx5</i> leads to aberrant lung bud and trachea specification.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-08-02 02:16:04"}
  • {"files"=>["https://ndownloader.figshare.com/files/598377"], "description"=>"<p>(A–G) Alcian blue staining was used to visualize tracheal/bronchial cartilage. Ten-eleven cartilage rings were seen in control tracheas (E18.5, A); normal (arrow) and incomplete rings were seen in tracheas and bronchi (black and red arrowheads respectively) of lung-specific <i>Tbx5</i> null (E18.5, B) and lung-specific <i>Tbx4</i> heterozygous;<i>Tbx5</i> nulls (postnatal day (P) 0, C). Asterisks in (A–C) indicate the point of bronchial separation from the trachea. Alcian blue on P0 sections showed that the control trachea (D) and main stem bronchial lumens (E) were expanded and the chondrocytes were present as C shaped rings (arrowheads). The lung-specific <i>Tbx4</i> heterozygous;<i>Tbx5</i> null tracheal lumen (F) and main stem bronchial lumen (G) were collapsed and filled with a mucus like substance (arrows) and alcian blue positive foci were seen (black arrowheads). Higher magnification views of control (D′,D″) and lung-specific <i>Tbx4</i> heterozygous;<i>Tbx5</i> null (F′,F″) tracheas. Yellow arrowheads indicate alcian blue positive mucus-producing cells in the lung-specific <i>Tbx4</i> heterozygous;<i>Tbx5</i> null tracheas. TL, Tracheal lumen; RBL, Right bronchial lumen; LBL, Left bronchial lumen. (H–S) Genes important for chondrogenesis and smooth muscle development. <i>Sox9</i> expression at E12.5 showed a comparable ventral expression pattern in control (H) and lung-specific <i>Tbx4</i> heterozygous;<i>Tbx5</i> null tracheas (I). At E13.5, <i>Sox9</i> positive cells begin to condense and appear in a ring like pattern in controls (J) but not in the mutant tracheas (K). <i>Sox6</i> (L,M) and <i>Sox5</i> (N,O) expression was downregulated in the lung-specific <i>Tbx4</i> heterozygous;<i>Tbx5</i> null tracheas at E13.5. <i>Col2α1</i> was expressed in its characteristic ring like pattern (P) similar to <i>Sox9</i> in the control tracheas but there were fewer rings with apparently normal expression in the lung-specific <i>Tbx4</i> heterozygous;<i>Tbx5</i> null tracheas (Q). <i>SM22α</i> expression was analyzed on the dorsal trachea at E13.5 in the control (R) and in the lung-specific <i>Tbx4</i> heterozygous;<i>Tbx5</i> null tracheas (S). Arrowheads in (S) point to ectopic expression in an uncharacteristic pattern in the mutants. Scale bars represent 100 µm.</p>", "links"=>[], "tags"=>["disrupts", "cartilage"], "article_id"=>268872, "categories"=>["Medicine", "Genetics", "Developmental Biology"], "users"=>["Ripla Arora", "Ross J. Metzger", "Virginia E. Papaioannou"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1002866.g007", "stats"=>{"downloads"=>2, "page_views"=>29, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Loss_of_Tbx4_and_Tbx5_disrupts_tracheal_bronchial_cartilage_and_smooth_muscle_formation_/268872", "title"=>"Loss of <i>Tbx4</i> and <i>Tbx5</i> disrupts tracheal/bronchial cartilage and smooth muscle formation.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-08-02 02:27:52"}
  • {"files"=>["https://ndownloader.figshare.com/files/597545"], "description"=>"<p>(A–L) <i>Tbx4</i> and <i>Tbx5</i> expression analyzed using ISH on lungs. <i>Tbx5</i> is first expressed at E9.0 (B,D) when the specification of lung primordia occurs, as seen by <i>Nkx2.1</i> expression (A,C). Red arrows point to the posterior extent of the third pharyngeal pouch which marks the anterior of the expression domain of both <i>Nkx2.1</i> and <i>Tbx5</i>. Right views (A,B), ventral views (C,D). <i>Tbx4</i> is first expressed at E9.5 along with <i>Tbx5</i> in the newly formed lung buds (E,F). Expression is seen in lung whole mounts at E11.5 (G,H), E13.5 (I,J) and in lung mesenchyme in cryosections at E15.5 (K,L). (M–S) <i>Tbx4</i> and <i>Tbx5</i> expression analyzed using ISH on tracheas. <i>Tbx4</i> and <i>Tbx5</i> are expressed throughout tracheal mesenchyme (m) at E13.5 (M,M′,N,N′) but not in the epithelium (e) or the mesothelium (arrowheads). Caudal view of cut tracheas after whole mount ISH (M–P). ISH on cryosections (M′–P′). At E13.5, <i>Sox9</i> is expressed in the mesenchyme on the ventral side (O,O′) and <i>SM22α</i> is expressed on the dorsal side (P,P′) of the trachea. D-dorsal; V-ventral; R-right; L-left. At E15.5, <i>Tbx4</i> and <i>Tbx5</i> are expressed around the condensing cartilage mesenchyme and in the intercartilage mesenchyme (Q,R). <i>Sox9</i> is expressed in the condensing cartilage rings (S). Asterisks indicate areas of cartilage condensation. Insets in (Q) and (S) show ISH on E15.5 sagittal cryosections with <i>Tbx4</i> and <i>Sox9</i> probe, respectively. Scale bars represent 50 µm.</p>", "links"=>[], "tags"=>["genetics and genomics", "developmental biology", "respiratory medicine"], "article_id"=>268040, "categories"=>["Medicine", "Genetics", "Developmental Biology"], "users"=>["Ripla Arora", "Ross J. Metzger", "Virginia E. Papaioannou"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1002866.g001", "stats"=>{"downloads"=>1, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Expression_of_Tbx4_and_Tbx5_in_the_developing_lung_and_trachea_/268040", "title"=>"Expression of <i>Tbx4</i> and <i>Tbx5</i> in the developing lung and trachea.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-08-02 02:14:00"}
  • {"files"=>["https://ndownloader.figshare.com/files/598259"], "description"=>"<p>(A–E) Lungs of different genotypes at E18.5. <i>Tbx4</i>;<i>Tbx5</i> double heterozygous lungs (B) are smaller than control lungs (A). <i>Tbx4</i>;<i>Tbx5</i>;<i>Fgf10</i> triple heterozygous lungs (C) are smaller than the double heterozygous lungs (B) but comparable in size to the lung-specific <i>Tbx4</i> heterozyous;<i>Tbx5</i> null lungs (D). Removing an additional copy of Fgf10 from the lung-specific <i>Tbx4</i> heterozyous;<i>Tbx5</i> null lungs does not further affect lung size (E). ht, heart. (F–I) <i>E-cad</i> expression in epithelium of the control lungs and conditional double null lungs in the absence (F,G) and presence (H,I) of exogeneous Fgf10 showing a lack of rescue of branching morphogenesis. (J–M) <i>Etv5</i> expression in control lungs and conditional double null lungs in the absence (J,K) and presence (L,M) of exogeneous Fgf10. <i>Etv5</i> expression remains unchanged after addition of Fgf10. (N,O) Both control and conditional double null lungs respond to FGF10 coated beads (f) but not to BSA coated beads (b) as seen by swelling of tips (arrows) in proximity to the FGF10 bead.</p>", "links"=>[], "tags"=>["fgf10", "fails"], "article_id"=>268752, "categories"=>["Medicine", "Genetics", "Developmental Biology"], "users"=>["Ripla Arora", "Ross J. Metzger", "Virginia E. Papaioannou"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1002866.g006", "stats"=>{"downloads"=>1, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Tbx4_and_Tbx5_interact_with_Fgf10_but_FGF10_fails_to_rescue_Tbx4_and_Tbx5_deficient_lungs_/268752", "title"=>"<i>Tbx4</i> and <i>Tbx5</i> interact with <i>Fgf10</i>, but FGF10 fails to rescue <i>Tbx4-</i> and <i>Tbx5</i>-deficient lungs.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-08-02 02:25:52"}
  • {"files"=>["https://ndownloader.figshare.com/files/312360", "https://ndownloader.figshare.com/files/312380", "https://ndownloader.figshare.com/files/312790"], "description"=>"<div><p>Normal development of the respiratory system is essential for survival and is regulated by multiple genes and signaling pathways. Both <em>Tbx4</em> and <em>Tbx5</em> are expressed throughout the mesenchyme of the developing lung and trachea; and, although multiple genes are known to be required in the epithelium, only Fgfs have been well studied in the mesenchyme. In this study, we investigated the roles of <em>Tbx4</em> and <em>Tbx5</em> in lung and trachea development using conditional mutant alleles and two different Cre recombinase transgenic lines. Loss of <em>Tbx5</em> leads to a unilateral loss of lung bud specification and absence of tracheal specification in organ culture. Mutants deficient in <em>Tbx4</em> and <em>Tbx5</em> show severely reduced lung branching at mid-gestation. Concordant with this defect, the expression of mesenchymal markers <em>Wnt2</em> and <em>Fgf10</em>, as well as Fgf10 target genes <em>Bmp4</em> and <em>Spry2</em>, in the epithelium is downregulated. Lung branching undergoes arrest <em>ex vivo</em> when <em>Tbx4</em> and <em>Tbx5</em> are both completely lacking. Lung-specific <em>Tbx4</em> heterozygous;<em>Tbx5</em> conditional null mice die soon after birth due to respiratory distress. These pups have small lungs and show severe disruptions in tracheal/bronchial cartilage rings. <em>Sox9</em>, a master regulator of cartilage formation, is expressed in the trachea; but mesenchymal cells fail to condense and consequently do not develop cartilage normally at birth. <em>Tbx4</em>;<em>Tbx5</em> double heterozygous mutants show decreased lung branching and fewer tracheal cartilage rings, suggesting a genetic interaction. Finally, we show that <em>Tbx4</em> and <em>Tbx5</em> interact with <em>Fgf10</em> during the process of lung growth and branching but not during tracheal/bronchial cartilage development.</p> </div>", "links"=>[], "tags"=>["roles", "interactions", "respiratory"], "article_id"=>121617, "categories"=>["Medicine", "Genetics", "Developmental Biology"], "users"=>["Ripla Arora", "Ross J. Metzger", "Virginia E. Papaioannou"], "doi"=>["https://dx.doi.org/10.1371/journal.pgen.1002866.s001", "https://dx.doi.org/10.1371/journal.pgen.1002866.s002", "https://dx.doi.org/10.1371/journal.pgen.1002866.s003"], "stats"=>{"downloads"=>3, "page_views"=>10, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Multiple_Roles_and_Interactions_of_Tbx4_and_Tbx5_in_Development_of_the_Respiratory_System/121617", "title"=>"Multiple Roles and Interactions of <em>Tbx4</em> and <em>Tbx5</em> in Development of the Respiratory System", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2012-08-02 00:26:57"}
  • {"files"=>["https://ndownloader.figshare.com/files/598521"], "description"=>"<p>Alcian blue staining was used to analyze tracheal/bronchial cartilage development in tracheas from different genotypes at E18.5. Control tracheas (A), <i>Tbx4</i>;<i>Fgf10</i> double heterozygous tracheas (B) and <i>Tbx5</i>;<i>Fgf10</i> double heterozygous tracheas (C) have 10–11 C-shaped, ventral tracheal cartilage rings and the trachea forms the two main stem bronchi which have lateral C-shaped cartilage rings. <i>Fgf10</i> homozygous mutants (D), <i>Tbx4</i>;<i>Tbx5</i> double heterozygous mutants (E) and <i>Tbx4</i>;<i>Tbx5</i>;<i>Fgf10</i> triple heterozygous mutants (F) each form fewer (6–8) tracheal cartilage rings, some irregularly shaped or incomplete (arrowheads). Additionally, <i>Fgf10</i> mutants lack bronchi and hence any bronchial cartilage rings (D), but the double and triple heterozygotes form normal lateral bronchial cartilage rings (arrows in E and F). Lung-specific <i>Tbx4</i> heterozygous;<i>Tbx5</i> nulls (G) show severe disruptions in formation of tracheal/bronchial cartilage rings, a phenotype that is unchanged with the removal of an <i>Fgf10</i> allele (H). Asterisk shows the point of bronchial separation from the trachea.</p>", "links"=>[], "tags"=>["interactions", "trachea"], "article_id"=>269015, "categories"=>["Medicine", "Genetics", "Developmental Biology"], "users"=>["Ripla Arora", "Ross J. Metzger", "Virginia E. Papaioannou"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1002866.g008", "stats"=>{"downloads"=>1, "page_views"=>29, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Lack_of_genetic_interactions_between_Tbx4_Tbx5_and_Fgf10_in_trachea_formation_/269015", "title"=>"Lack of genetic interactions between <i>Tbx4</i>, <i>Tbx5</i>, and <i>Fgf10</i> in trachea formation.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-08-02 02:30:15"}
  • {"files"=>["https://ndownloader.figshare.com/files/598584"], "description"=>"<p>(A) Lung and trachea specification begins at E9.0 in the ventral foregut and at this time <i>Tbx5</i> expression (light purple) is adjacent to the presumptive endoderm. Later, <i>Tbx4</i> and <i>Tbx5</i> expression (dark purple) is in mesenchyme associated with the lung and trachea. <i>Tbx5</i> but not <i>Tbx4</i> is important for specification of bilateral lung buds and the trachea. (B) Magnification of box shown in (A) representing the events in the growing tip during branching morphogenesis. Grey denotes epithelium and purple denotes mesenchyme. <i>Tbx4</i> and <i>Tbx5</i> interact with each other and act upstream of the Fgf10 signaling pathway. Decrease in <i>Tbx4</i> and <i>Tbx5</i> affects mesenchymal <i>Fgf10</i> expression and expression of its targets in the epithelium – <i>Bmp4</i>, <i>Spry2</i> and <i>Etv5</i> – but not the expression of the epithelial Fgf10 receptor <i>Fgfr2</i>. In addition to <i>Fgf10</i> expression in the mesenchyme, <i>Tbx4</i> and <i>Tbx5</i> also control the expression of an unknown factor(s) (X) that is essential for activation of the Fgf10 signaling pathway. Furthermore, <i>Tbx4</i> and <i>Tbx5</i> act upstream of <i>Wnt2</i> in the mesenchyme. (C) In the trachea and the main stem bronchi <i>Tbx4</i> and <i>Tbx5</i> either control <i>Sox9</i> expression, which in turn regulates cartilage condensation, or <i>Tbx4</i> and <i>Tbx5</i> regulate another factor (X) essential for chondrogenesis secondarily affecting <i>Sox9</i> expression.</p>", "links"=>[], "tags"=>["trachea"], "article_id"=>269080, "categories"=>["Medicine", "Genetics", "Developmental Biology"], "users"=>["Ripla Arora", "Ross J. Metzger", "Virginia E. Papaioannou"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1002866.g009", "stats"=>{"downloads"=>1, "page_views"=>11, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Model_for_the_role_of_Tbx4_and_Tbx5_in_lung_and_trachea_development_/269080", "title"=>"Model for the role of <i>Tbx4</i> and <i>Tbx5</i> in lung and trachea development.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-08-02 02:31:20"}
  • {"files"=>["https://ndownloader.figshare.com/files/597917"], "description"=>"<p>Lung buds were isolated at E11.5 and cultured in the presence of 4-OH tamoxifen. At the end of the culture airways were visualized using <i>E-cadherin</i> ISH. Conditional <i>Tbx4</i> homozygous;<i>Tbx5</i> heterozygous (B) and conditional <i>Tbx4</i> heterozygous;<i>Tbx5</i> null (C) lungs with <i>CreER</i> showed reduced branching after 4 days of culture compared to controls (A). Control, without <i>CreER</i>, (D) and conditional double null lung buds, with <i>CreER</i>, (E) were cultured for 4 days and photographed at 1 day, 2 days, 3 days and 4 days. Arrows in E show the progression of an elongating airway. A plot of the number of branching tips as a function of time for controls and the conditional double nulls (F), shows a branching arrest of the conditional double null lungs after 2 days of culture (Mann Whitney U test p = 0.036).</p>", "links"=>[], "tags"=>["leads", "branching"], "article_id"=>268412, "categories"=>["Medicine", "Genetics", "Developmental Biology"], "users"=>["Ripla Arora", "Ross J. Metzger", "Virginia E. Papaioannou"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1002866.g004", "stats"=>{"downloads"=>0, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Loss_of_Tbx4_and_Tbx5_leads_to_branching_arrest_ex_vivo_/268412", "title"=>"Loss of <i>Tbx4</i> and <i>Tbx5</i> leads to branching arrest <i>ex vivo</i>.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-08-02 02:20:12"}
  • {"files"=>["https://ndownloader.figshare.com/files/597790"], "description"=>"<p>(A–H′) <i>Tbx4<sup>fl</sup></i> and <i>Tbx5<sup>fl</sup></i> alleles were excised using <i>CreER</i> by injecting tamoxifen at E8.75 and lungs were dissected at different time points. Loss of <i>Tbx4</i> alone or both <i>Tbx4</i> and <i>Tbx5</i> leads to lung hypoplasia at E13.5 (A–D). The number of branching tips was quantitated following E-cadherin staining for different genotypes at E12.5 (E) and E13.5 (F). H & E on histological sections shows a decrease in lung size at E12.5 in the conditional <i>Tbx4</i> null;<i>Tbx5</i> heterozygous lungs (G,H,). (G′) and (H′) are magnified views of the boxed regions in (G) and (H), respectively. Black arrowheads indicate separation between the lobes of the right lung in the control (G′) and lack of separation in the mutants (H′). (I–Q) <i>Tbx4<sup>cre</sup></i> was utilized for lung and trachea-specific excision of <i>Tbx4<sup>fl</sup></i> and <i>Tbx5<sup>fl</sup></i> alleles. <i>Tbx4<sup>cre</sup></i> was expressed in most of the trachea mesenchyme (I) and lung mesenchymal cells (J) as seen by a <i>R26RlacZ</i> reporter expression at E13.5. Lung-specific <i>Tbx4</i> heterozygous;<i>Tbx5</i> null lungs show hypoplasia at E13.5 (K,L) and at birth (N,O). The number of branching tips in control lungs and the lung-specific <i>Tbx4</i> heterozygous;<i>Tbx5</i> null lungs, labeled as experimental in the box plot (M), are significantly different at E13.5. The green boxes contain 50% of the values; the median is indicated by a horizontal line in the box; bars represent the 5<sup>th</sup> and 95<sup>th</sup> percentiles. H & E staining on sections shows lung morphology for control (P) and mutants (Q) at birth. Scale bars represent 100 µm.</p>", "links"=>[], "tags"=>["causes", "reduced", "branching", "lethality"], "article_id"=>268285, "categories"=>["Medicine", "Genetics", "Developmental Biology"], "users"=>["Ripla Arora", "Ross J. Metzger", "Virginia E. Papaioannou"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1002866.g003", "stats"=>{"downloads"=>1, "page_views"=>12, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Loss_of_Tbx4_and_Tbx5_causes_reduced_lung_branching_and_lethality_at_birth_/268285", "title"=>"Loss of <i>Tbx4</i> and <i>Tbx5</i> causes reduced lung branching and lethality at birth.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-08-02 02:18:05"}

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  • {"unique-ip"=>"11", "full-text"=>"11", "pdf"=>"5", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2017", "month"=>"6"}
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  • {"unique-ip"=>"20", "full-text"=>"21", "pdf"=>"8", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"2", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"4"}
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  • {"unique-ip"=>"13", "full-text"=>"11", "pdf"=>"4", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"8"}
  • {"unique-ip"=>"15", "full-text"=>"18", "pdf"=>"5", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"1", "year"=>"2019", "month"=>"9"}
  • {"unique-ip"=>"27", "full-text"=>"27", "pdf"=>"2", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"9", "supp-data"=>"0", "cited-by"=>"1", "year"=>"2019", "month"=>"10"}
  • {"unique-ip"=>"24", "full-text"=>"13", "pdf"=>"12", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"1", "supp-data"=>"3", "cited-by"=>"0", "year"=>"2019", "month"=>"12"}
  • {"unique-ip"=>"22", "full-text"=>"21", "pdf"=>"7", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"19", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2020", "month"=>"2"}
  • {"unique-ip"=>"14", "full-text"=>"13", "pdf"=>"4", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2020", "month"=>"3"}
  • {"unique-ip"=>"19", "full-text"=>"20", "pdf"=>"3", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"1", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2020", "month"=>"4"}

Relative Metric

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