Nkx2.5 and Nkx2.6, Homologs ofDrosophila tinman, Are Required for Development of the Pharynx

ABSTRACT Nkx2.5 and Nkx2.6 are murine homologs of Drosophilatinman. Their genes are expressed in the ventral region of the pharynx at early stages of embryogenesis. However, no abnormalities in the pharynges of embryos with mutations in either Nkx2.5 or Nkx2.6 have been reported. To examine the function of Nkx2.5 and Nkx2.6 in the formation of the pharynx, we generated and analyzed Nkx2.5 and Nkx2.6 double-mutant mice. Interestingly, in the double-mutant embryos, the pharynx did not form properly. Pharyngeal endodermal cells were largely missing, and the mutant pharynx was markedly dilated. Moreover, we observed enhanced apoptosis and reduced proliferation in pharyngeal endodermal cells of the double-mutant embryos. These results demonstrated a critical role of the NK-2 homeobox genes in the differentiation, proliferation, and survival of pharyngeal endodermal cells. Furthermore, the development of the atrium was less advanced in the double-mutant embryos, indicating that these two genes are essential for both pharyngeal and cardiac development.

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Abstract 791: A Critical Role for Bmper (BMP-binding Endothelial cell precursor-derived Regulator) in Cardiac Muscle Mass Regulation during Development and Pressure Overload Induced Hypertrophy

Circulation ◽

10.1161/circ.116.suppl_16.ii_152-c ◽

2007 ◽

Vol 116 (suppl_16) ◽

Author(s):

Monte Willis ◽

Rongqin Ren ◽

Cam Patterson

Keyword(s):

Cardiac Function ◽

Cardiac Muscle ◽

Muscle Mass ◽

Cardiac Development ◽

Critical Role ◽

Pressure Overload ◽

Posterior Wall ◽

Fractional Shortening

Bone morphogenetic proteins (BMPs) of the TGF-beta superfamily, have been implicated in multiple processes during cardiac development. Our laboratory recently described an unprecedented role for Bmper in antagonizing BMP-2, BMP-4, and BMP-6. To determine the role of Bmper on cardiac development in vivo, we created Bmper null (Bmper −/−) mice by replacing exons 1 and 2 with GFP. Since Bmper −/− mice are perinatally lethal, we determined pre-natal cardiac function of Bmper −/− mice in utero just before birth. By echocardiography, E18.5 Bmper −/− embryos had decreased cardiac function (24.2 +/− 8.1% fractional shortening) compared to Bmper +/− and Bmper +/+ siblings (52.2 +/− 1.6% fractional shortening) (N=4/group). To further characterize the role of Bmper on cardiac function in adult mice, we performed echocardiography on 8-week old male and female Bmper +/− and littermate control Bmper +/+. Bmper +/− mice had an approximately 15% decrease in anterior and posterior wall thickness compared to sibling Bmper +/+ mice at baseline (n=10/group). Cross-sectional areas of Bmper +/− cardiomyocytes were approximately 20% less than wild type controls, indicating cardiomyocyte hypoplasia in adult Bmper +/− mice at baseline. Histologically, no significant differences were identified in representative H&E and trichrome stained adult Bmper +/− and Bmper +/+ cardiac sections at baseline. To determine the effects of Bmper expression on the development of cardiac hypertrophy, both Bmper +/− and Bmper +/+ sibling controls underwent transaortic constriction (TAC), followed by weekly echocardiography. While a deficit was identified in Bmper +/− mice at baseline, both anterior and posterior wall thicknesses increased after TAC, such that identical wall thicknesses were identified in Bmper +/− and Bmper +/+ mice 1–4 weeks after TAC. Notably, cardiac function (fractional shortening %) and histological evaluation revealed no differences between Bmper +/− and Bmper +/+ any time after TAC. These studies identify for the first time that Bmper expression plays a critical role in regulating cardiac muscle mass during development, and that Bmper regulates the development of hypertrophy in response to pressure overload in vivo.

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Impairment of the p27kip1 function enhances thyroid carcinogenesis in TRK-T1 transgenic mice

Endocrine Related Cancer ◽

10.1677/erc-08-0272 ◽

2009 ◽

Vol 16 (2) ◽

pp. 483-490 ◽

Cited By ~ 11

Author(s):

Monica Fedele ◽

Dario Palmieri ◽

Gennaro Chiappetta ◽

Rosa Pasquinelli ◽

Ivana De Martino ◽

...

Keyword(s):

Thyroid Cancer ◽

Papillary Thyroid Cancer ◽

Double Mutant ◽

Null Allele ◽

Latency Period ◽

Mutant Mice ◽

Proliferation Index ◽

Papillary Thyroid ◽

Thyroid Carcinomas

Impairment of the p27kip1 function, caused by a drastic reduction of its expression or cytoplasmic mislocalization, has been frequently observed in thyroid carcinomas. To understand the role of p27kip1 impairment in thyroid carcinogenesis, we investigated the consequences of the loss of p27kip1 expression in the context of a mouse modeling of papillary thyroid cancer, expressing the TRK-T1 oncogene under the transcriptional control of thyroglobulin promoter. We found that double mutant mice homozygous for a p27kip1 null allele (TRK-T1/p27−/−) display a higher incidence of papillary thyroid carcinomas, with a shorter latency period and increased proliferation index, compared with p27kip1 wild-type compounds (TRK-T1/p27+/+). Consistently, double mutant mice heterozygous for a p27kip1 null allele (TRK-T1/p27+/−) show an incidence of thyroid carcinomas that is intermediate between TRK-T1/p27−/− and TRK-T1/p27+/+ mice. Therefore, our findings suggest a dose-dependent role of p27kip1 function in papillary thyroid cancer development.

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On the Key Role of Secondary Lymphoid Organs in Antiviral Immune Responses Studied in Alymphoplastic (aly/aly) and Spleenless (Hox11−/−) Mutant Mice

Journal of Experimental Medicine ◽

10.1084/jem.185.12.2157 ◽

1997 ◽

Vol 185 (12) ◽

pp. 2157-2170 ◽

Cited By ~ 151

Author(s):

Urs Karrer ◽

Alana Althage ◽

Bernhard Odermatt ◽

Charles W.M. Roberts ◽

Stanley J. Korsmeyer ◽

...

Keyword(s):

B Cells ◽

Immune Responses ◽

Critical Role ◽

Homeobox Gene ◽

Lymphocytic Choriomeningitis ◽

Lymphoid Organs ◽

Mutant Mice ◽

Virus Infections ◽

Secondary Lymphoid Organs

The role of the spleen and of other organized secondary lymphoid organs for the induction of protective antiviral immune responses was evaluated in orphan homeobox gene 11 knockout mice (Hox11−/−) lacking the spleen, and in homozygous alymphoplastic mutant mice (aly/aly) possessing a structurally altered spleen but lacking lymph nodes and Peyer's patches. Absence of the spleen had no major effects on the immune response, other than delaying the antibody response by 1–2 d. In aly/aly mice, the thymus-independent IgM response against vesicular stomatitis virus (VSV) was delayed and reduced, whereas the T-dependent switch to the protective IgG was absent. Therefore, aly/aly mice were highly susceptible to VSV infection. Since aly/aly spleen cells yielded neutralizing IgM and IgG after adoptive transfer into recipients with normally structured secondary lymphoid organs, these data suggest that the structural defect was mainly responsible for inefficient T–B cooperation. Although aly/aly mice generated detectable, but reduced, CTL responses after infection with vaccinia virus (VV) and lymphocytic choriomeningitis virus (LCMV), the elimination of these viruses was either delayed (VV) or virtually impossible (LCMV); irrespective of the dose or the route of infection, aly/aly mice developed life-long LCMV persistence. These results document the critical role of organized secondary lymphoid organs in the induction of naive T and B cells. These structures also provide the basis for cooperative interactions between antigen-presenting cells, T cells, and B cells, which are a prerequisite for recovery from primary virus infections via skin or via blood.

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LRRTM1 underlies synaptic convergence in visual thalamus

10.1101/221200 ◽

2017 ◽

Author(s):

Aboozar Monavarfeshani ◽

Gail Stanton ◽

Jonathan Van Name ◽

Kaiwen Su ◽

William A. Mills ◽

...

Keyword(s):

Ganglion Cells ◽

Critical Role ◽

Mutant Mice ◽

Visual Signals ◽

Color Contrast ◽

Specific Information ◽

Retinal Ganglion ◽

Thalamic Relay ◽

Visual Behaviors

AbstractIt has long been thought that the mammalian visual system is organized into parallel pathways, with incoming visual signals being parsed in the retina based on feature (e.g. color, contrast and motion) and then transmitted to the brain in unmixed, feature-specific channels. To faithfully convey feature-specific information from retina to cortex, thalamic relay cells must receive inputs from only a small number of functionally similar retinal ganglion cells. However, recent studies challenged this by revealing substantial levels of retinal convergence onto relay cells. Here, we sought to identify mechanisms responsible for the assembly of such convergence. Using an unbiased transcriptomics approach and targeted mutant mice, we discovered a critical role for the synaptic adhesion molecule Leucine Rich Repeat Transmembrane Neuronal 1 (LRRTM1) in the emergence of retinothalamic convergence. Importantly, LRRTM1 mutant mice display impairment in visual behaviors, suggesting a functional role of retinothalamic convergence in vision.

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The Role of Cardiac Fibroblasts in Extracellular Matrix-Mediated Signaling During Normal and Pathological Cardiac Development

Journal of Biomechanical Engineering ◽

10.1115/1.4024349 ◽

2013 ◽

Vol 135 (7) ◽

Cited By ~ 29

Author(s):

Kelly Elizabeth Sullivan ◽

Lauren Deems Black

Keyword(s):

Extracellular Matrix ◽

Cardiac Development ◽

Cardiac Fibroblasts ◽

Heart Defects ◽

Critical Role ◽

Heart Tissue ◽

Physical And Chemical

The extracellular matrix is no longer considered a static support structure for cells but a dynamic signaling network with the power to influence cell, tissue, and whole organ physiology. In the myocardium, cardiac fibroblasts are the primary cell type responsible for the synthesis, deposition, and degradation of matrix proteins, and they therefore play a critical role in the development and maintenance of functional heart tissue. This review will summarize the extensive research conducted in vivo and in vitro, demonstrating the influence of both physical and chemical stimuli on cardiac fibroblasts and how these interactions impact both the extracellular matrix and, by extension, cardiomyocytes. This work is of considerable significance, given that cardiovascular diseases are marked by extensive remodeling of the extracellular matrix, which ultimately impairs the functional capacity of the heart. We seek to summarize the unique role of cardiac fibroblasts in normal cardiac development and the most prevalent cardiac pathologies, including congenital heart defects, hypertension, hypertrophy, and the remodeled heart following myocardial infarction. We will conclude by identifying existing holes in the research that, if answered, have the potential to dramatically improve current therapeutic strategies for the repair and regeneration of damaged myocardium via mechanotransductive signaling.

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Critical Role of the Gab2/PI3K/mTOR Pathway in the Pathogenesis of Ptpn11 (Shp2) Mutation-Induced Myeloproliferative Disease.

Blood ◽

10.1182/blood.v120.21.2856.2856 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2856-2856

Author(s):

Wei Liu ◽

Xia Liu ◽

Cheng-Kui Qu

Keyword(s):

Double Mutant ◽

Hematological Malignancies ◽

Mtor Pathway ◽

Mutant Mice ◽

Juvenile Myelomonocytic Leukemia ◽

Myeloproliferative Disease ◽

Acute Leukemias ◽

Pathogenic Effects ◽

Myeloid Progenitors

Abstract Abstract 2856 Germline and somatic mutations (heterozygous) in Ptpn11 (Shp2), a protein tyrosine phosphatase implicated in multiple cell signaling processes, have been identified in juvenile myelomonocytic leukemia (JMML), a childhood myeloproliferative disease (MPD), and pediatric acute leukemias. These mutations cause hyperactivation of Shp2 catalytic activity and enhance the binding of mutant Shp2 to signaling partners. Ptpn11 mutations are sufficient to drive the development of JMML-like MPD and acute leukemias in mice, suggesting that they play a causal role in the pathogenesis of hematological malignancies. However, the mechanisms by which Ptpn11 mutations induce these malignancies are not completely understood and the signaling partners that mediate the pathogenic effects of Ptpn11 mutations have not been explored. We previously generated a line of conditional knock-in mice with Ptpn11E76K mutation, the most common and most active Ptpn11 mutation found in JMML and acute leukemias. Induced knock-in of this mutation in hematopoietic cells resulted in MPD with full penetrance as a result of aberrant activation of hematopoietic stem cells (HSCs) and myeloid progenitors (J. Exp. Med., 2011). Recently, we discovered that the interaction between Shp2 E76K and Gab2, a prominent interacting protein of Shp2 and a scaffolding protein important for cytokine-induced PI3K/Akt/mTOR signaling, was greatly enhanced, and that mTOR was highly activated in Ptpn11E76K/+ MPD cells. To address the role of Gab2 and mTOR in the pathogenesis of Ptpn11E76K/+ mutation-induced MPD, Ptpn11E76K/+/Gab2-/- double mutant mice were generated and their phenotypes were compared with those of Ptpn11E76K/+ single mutant mice. MPD phenotypes were markedly attenuated in Ptpn11E76K/+/Gab2-/- double mutant mice. Overproduction of myeloid cells in the bone marrow was alleviated, and splenomegaly was diminished in the double mutants. Myeloid cell infiltration in the liver also decreased. Cytokine (IL-3 and GM-CSF) sensitivity of myeloid progenitors was significantly decreased in Ptpn11E76K/+/Gab2−/− mice as compared to that in Ptpn11E76K/+ mice. Hyperactivation of HSCs and excessive myeloid differentiation caused by Ptpn11E76K mutation were largely corrected by deletion of Gab2. Furthermore, we treated Ptpn11E76K/+ mice with Rapmycin, a specific and potent mTOR inhibitor, which substantially diminished MPD phenotypes. Collectively, this study reveals the essential role of the Gab2/PI3K/mTOR pathway in mediating the pathogenic effects of Ptpn11E76K/+ mutation and suggests that Gab2 and mTOR are potential therapeutic targets for the treatment of Ptpn11-associated hematological malignancies. Disclosures: No relevant conflicts of interest to declare.

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The role of the homeobox gene, HOX B7, in human myelomonocytic differentiation

Blood ◽

10.1182/blood.v85.3.692.bloodjournal853692 ◽

1995 ◽

Vol 85 (3) ◽

pp. 692-697 ◽

Cited By ~ 49

Author(s):

MC Lill ◽

JF Fuller ◽

R Herzig ◽

GM Crooks ◽

JC Gasson

Keyword(s):

Cell Line ◽

Vitamin D3 ◽

Critical Role ◽

Homeobox Genes ◽

Homeobox Gene ◽

Hl60 Cell ◽

Monocytic Differentiation ◽

Granulocytic Differentiation ◽

Gm Csf

Homeobox genes encode transcription factors known to be important morphogenic regulators during embryogenesis. An increasing body of work implies a role for homeobox genes in both hematopoiesis and oncogenesis. We have analyzed the role of the homeobox gene, HOX B7, in the program of differentiation of the biphenotypic myeloid cell line, HL60. Induction of monocytic differentiation in HL-60 cells by vitamin D3 resulted in rapid expression of HOX B7 mRNA, but stimulation with phorbol ester or dimethyl sulfoxide (DMSO) did not. Constitutive overexpression of HOX B7 in the HL60 cell line inhibited the granulocytic differentiation associated with stimulation with DMSO or retinoic acid, but had no effect on the monocytic differentiation induced by vitamin D3. Normal human monocytes do not constitutively express HOX B7, nor are they able to be induced to do so by stimulation with colony-stimulating factor 1 (CSF-1) and gamma interferon (IFN gamma), or with vitamin D3 and lipopolysaccharide. Human bone marrow (BM) cells were found to express HOX B7 in response to granulocyte- macrophage CSF (GM-CSF) and antisense oligonucleotides directed against HOX B7 inhibited the formation of colonies derived from GM-CSF- stimulated BM. These data suggest a critical role for HOX B7 in myelomonocytic differentiation.

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Myocardial extra-cellular matrix and its regulation by metalloproteinases and their inhibitors

Thrombosis and Haemostasis ◽

10.1160/th04-08-0522 ◽

2005 ◽

Vol 93 (02) ◽

pp. 212-219 ◽

Cited By ~ 55

Author(s):

Zamaneh Kassiri ◽

Rama Khokha

Keyword(s):

Heart Failure ◽

Cardiac Development ◽

Critical Role ◽

Left Ventricular ◽

Tissue Inhibitors Of Metalloproteinases ◽

Western World ◽

A Disintegrin And Metalloproteinase ◽

And Function ◽

Myocardial Injuries

SummaryCardiovascular disease poses a major health care burden in the Western world. Following myocardial injuries, ventricular remodelling and dysfunction ensue, which can eventually culminate in heart failure. An important event in left ventricular (LV) remodelling is alteration of the extracellular matrix (ECM) integrity, the structural network that interconnects the myocardial components. The critical role of ECM remodelling in cardiac dilation and heart failure was recognized more than a decade ago, and the molecular factors responsible for this process are now being explored. Abnormal ECM turnover is primarily brought about by an imbalance in the activity of matrix metalloproteinases (MMPs) that degrade ECM components, and their endogenous inhibitors, tissue inhibitors of metalloproteinases (TIMPs). Here we provide an overview of composition of the cardiac ECM, and alterations in ECM regulatory proteins, MMPs and TIMPs, in human heart disease. We also discuss the role of TIMPs, MMPs, and a disintegrin and metalloproteinase (ADAMs) enzymes in cardiac development and function as learned through genetically altered mouse models.

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Evidence for the Critical Role of Sucrose Synthase for Anoxic Tolerance of Maize Roots using a Double Mutant

PLANT PHYSIOLOGY ◽

10.1104/pp.116.4.1323 ◽

1998 ◽

Vol 116 (4) ◽

pp. 1323-1331 ◽

Cited By ~ 63

Author(s):

Bérénice Ricard ◽

Tara Van Toai ◽

Prem Chourey ◽

Pierre Saglio

Keyword(s):

Sucrose Synthase ◽

Double Mutant ◽

Critical Role ◽

Maize Roots

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Loss of mRor1 Enhances the Heart and Skeletal Abnormalities in mRor2-Deficient Mice: Redundant and Pleiotropic Functions of mRor1 and mRor2 Receptor Tyrosine Kinases

Molecular and Cellular Biology ◽

10.1128/mcb.21.24.8329-8335.2001 ◽

2001 ◽

Vol 21 (24) ◽

pp. 8329-8335 ◽

Cited By ~ 80

Author(s):

Masashi Nomi ◽

Isao Oishi ◽

Shuichi Kani ◽

Hiroaki Suzuki ◽

Takeru Matsuda ◽

...

Keyword(s):

Tyrosine Kinases ◽

Double Mutant ◽

Receptor Tyrosine Kinases ◽

Cardiac Development ◽

Mutant Mice ◽

Pubic Bone ◽

Respiratory Dysfunction ◽

Skeletal Abnormalities ◽

Pleiotropic Functions ◽

Deficient Mice

ABSTRACT The mammalian Ror family of receptor tyrosine kinases consists of two structurally related proteins, Ror1 and Ror2. We have shown that mRor2-deficient mice exhibit widespread skeletal abnormalities, ventricular septal defects in the heart, and respiratory dysfunction, leading to neonatal lethality (S. Takeuchi, K. Takeda, I. Oishi, M. Nomi, M. Ikeya, K. Itoh, S. Tamura, T. Ueda, T. Hatta, H. Otani, T. Terashima, S. Takada, H. Yamamura, S. Akira, and Y. Minami, Genes Cells 5:71–78, 2000). Here we show thatmRor1-deficient mice have no apparent skeletal or cardiac abnormalities, yet they also die soon after birth due to respiratory dysfunction. Interestingly,mRor1/mRor2 double mutant mice show markedly enhanced skeletal abnormalities compared withmRor2 mutant mice. Furthermore, double mutant mice also exhibit defects not observed in mRor2 mutant mice, including a sternal defect, dysplasia of the symphysis of the pubic bone, and complete transposition of the great arteries. These results indicate that mRor1 and mRor2 interact genetically in skeletal and cardiac development.

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