skip to main content
OSTI.GOV title logo U.S. Department of Energy
Office of Scientific and Technical Information

Title: CHARACTERIZING THE ROLE OF THE NELL1 GENE IN CARDIOVASCULAR DEVELOPMENT

Abstract

Nell1{sup 6R} is a chemically-induced point mutation in a novel cell-signaling gene, Nell1, which results in truncation of the protein and degradation of the Nell16R transcript. Earlier studies revealed that loss of Nell1 function reduces expression of numerous extracellular matrix (ECM) proteins required for differentiation of bone and cartilage precursor cells, thereby causing severe skull and spinal defects. Since skeletal and cardiovascular development are closely linked biological processes, this research focused on: a) examining Nell16R mutant mice for cardiovascular defects, b) determining Nell1 expression in fetal and adult hearts, and c) establishing how ECM genes affected by Nell1 infl uence heart development. Structural heart defects in Nell16R mutant fetuses were analyzed by heart length and width measurements and standard histological methods (haematoxylin and eosin staining). Nell1 expression was assayed in fetal and adult hearts using reverse transcription polymerase chain reaction (RT-PCR). A comprehensive bioinformatics analysis using public databases (Stanford SOURCE Search, Integrated Cartilage Gene Database, Mouse Genome Informatics, and NCBI UniGene) was undertaken to investigate the relationship between cardiovascular development and each of twentyeight genes affected by Nell1. Nell1-defi cient mice have signifi cantly enlarged hearts (particularly the heart width), dramatically reduced blood fl ow out of the heart andmore » unexpanded lungs. Isolation of total RNAs from hearts of adult (control and heterozygote) and fetal (control and homozygous mutant) mice have been completed and RT-PCR assays are in progress. The bioinformatics analysis showed that the majority of genes with reduced expression in Nell1-defi cient mice are normally expressed in the heart (79%; 22/28), blood vessels (71%; 20/28) and bone marrow (61%; 17/28). Moreover, mouse mutations in seven of these genes (Col15a1, Osf-2, Bmpr1a, Pkd1, Mfge8, Ptger4, Col5a1) manifest abnormalities in cardiovascular development. These data demonstrate for the fi rst time that Nell1 has a role in early mammalian cardiovascular development, mediated by its regulation of ECM proteins necessary for normal cell growth and differentiation. In addition, understanding the mechanisms by which Nell1 and its associated ECM genes affect the cardiovascular system can provide future strategies for the treatment of heart and blood vessel defects.« less

Authors:
;
Publication Date:
Research Org.:
DOESC (USDOE Office of Science (SC) (United States))
Sponsoring Org.:
USDOE Office of Science (SC)
OSTI Identifier:
1051829
Resource Type:
Journal Article
Resource Relation:
Journal Name: Journal of Undergraduate Research; Journal Volume: 7
Country of Publication:
United States
Language:
English

Citation Formats

Liu, L. Y., and Culiat, C. CHARACTERIZING THE ROLE OF THE NELL1 GENE IN CARDIOVASCULAR DEVELOPMENT. United States: N. p., 2007. Web.
Liu, L. Y., & Culiat, C. CHARACTERIZING THE ROLE OF THE NELL1 GENE IN CARDIOVASCULAR DEVELOPMENT. United States.
Liu, L. Y., and Culiat, C. Mon . "CHARACTERIZING THE ROLE OF THE NELL1 GENE IN CARDIOVASCULAR DEVELOPMENT". United States. doi:. https://www.osti.gov/servlets/purl/1051829.
@article{osti_1051829,
title = {CHARACTERIZING THE ROLE OF THE NELL1 GENE IN CARDIOVASCULAR DEVELOPMENT},
author = {Liu, L. Y. and Culiat, C.},
abstractNote = {Nell1{sup 6R} is a chemically-induced point mutation in a novel cell-signaling gene, Nell1, which results in truncation of the protein and degradation of the Nell16R transcript. Earlier studies revealed that loss of Nell1 function reduces expression of numerous extracellular matrix (ECM) proteins required for differentiation of bone and cartilage precursor cells, thereby causing severe skull and spinal defects. Since skeletal and cardiovascular development are closely linked biological processes, this research focused on: a) examining Nell16R mutant mice for cardiovascular defects, b) determining Nell1 expression in fetal and adult hearts, and c) establishing how ECM genes affected by Nell1 infl uence heart development. Structural heart defects in Nell16R mutant fetuses were analyzed by heart length and width measurements and standard histological methods (haematoxylin and eosin staining). Nell1 expression was assayed in fetal and adult hearts using reverse transcription polymerase chain reaction (RT-PCR). A comprehensive bioinformatics analysis using public databases (Stanford SOURCE Search, Integrated Cartilage Gene Database, Mouse Genome Informatics, and NCBI UniGene) was undertaken to investigate the relationship between cardiovascular development and each of twentyeight genes affected by Nell1. Nell1-defi cient mice have signifi cantly enlarged hearts (particularly the heart width), dramatically reduced blood fl ow out of the heart and unexpanded lungs. Isolation of total RNAs from hearts of adult (control and heterozygote) and fetal (control and homozygous mutant) mice have been completed and RT-PCR assays are in progress. The bioinformatics analysis showed that the majority of genes with reduced expression in Nell1-defi cient mice are normally expressed in the heart (79%; 22/28), blood vessels (71%; 20/28) and bone marrow (61%; 17/28). Moreover, mouse mutations in seven of these genes (Col15a1, Osf-2, Bmpr1a, Pkd1, Mfge8, Ptger4, Col5a1) manifest abnormalities in cardiovascular development. These data demonstrate for the fi rst time that Nell1 has a role in early mammalian cardiovascular development, mediated by its regulation of ECM proteins necessary for normal cell growth and differentiation. In addition, understanding the mechanisms by which Nell1 and its associated ECM genes affect the cardiovascular system can provide future strategies for the treatment of heart and blood vessel defects.},
doi = {},
journal = {Journal of Undergraduate Research},
number = ,
volume = 7,
place = {United States},
year = {Mon Jan 01 00:00:00 EST 2007},
month = {Mon Jan 01 00:00:00 EST 2007}
}
  • Mild hyperhomocysteinemia is an established risk factor for cardiovascular disease. Genetic aberrations in the cystathionine P-synthase (CBS) and methylenetetrahydrofolate reductase (MTHFR) genes may account for reduced enzyme activities and elevated plasma homocysteine levels. In 15 unrelated Dutch patients with homozygous CBS deficiency, we observed the 833T{yields}C (1278T) mutation in 50% of the alleles. Very recently, we identified a common mutation (677C{yields}T; A{yields}V) in the MTHFR gene, which, in homozygous state, is responsible for the thermolabile phenotype and which is associated with decreased specific MTHFR activity and elevated homocysteine levels. We screened 60 cardiovascular patients and 111 controls for these twomore » mutations, to determine whether these mutations are risk factors for premature cardiovascular disease. Heterozygosity for the 833T{yields}C mutation in the CBS gene was observed in one individual of the control group but was absent in patients with premature cardiovascular disease. Homozygosity for the 677C-{yields}T mutation in the MTHFR gene was found in 9 (15%) of 60 cardiovascular patients and in only 6 ({approximately}5%) of 111 control individuals (odds ratio 3.1 [95% confidence interval 1.0-9.21]). Because of both the high prevalence of the 833T-{yields}C mutation among homozygotes for CBS deficiency and its absence in 60 cardiovascular patients, we may conclude that heterozygosity for CBS deficiency does not appear to be involved in premature cardiovascular disease. However, a frequent homozygous mutation in the MTHFR gene is associated with a threefold increase in risk for premature cardiovascular disease. 35 refs., 3 figs., 1 tab.« less
  • Inorganic arsenic has been associated with increased risk of atherosclerotic vascular disease and mortality in humans. A functional GT-repeat polymorphism in the heme oxygenase-1 (HO-1) gene promoter is inversely correlated with the development of coronary artery disease and restenosis after clinical angioplasty. The relationship of HO-1 genotype with arsenic-associated cardiovascular disease has not been studied. In this study, we evaluated the relationship between the HO-1 GT-repeat polymorphism and cardiovascular mortality in an arsenic-exposed population. A total of 504 study participants were followed up for a median of 10.7 years for occurrence of cardiovascular deaths (coronary heart disease, cerebrovascular disease, andmore » peripheral arterial disease). Cardiovascular risk factors and DNA samples for determination of HO-1 GT repeats were obtained at recruitment. GT repeats variants were grouped into the S (< 27 repeats) or L allele ({>=} 27 repeats). Relative mortality risk was estimated using Cox regression analysis, adjusted for competing risk of cancer and other causes. For the L/L, L/S, and S/S genotype groups, the crude mortalities for cardiovascular disease were 8.42, 3.10, and 2.85 cases/1000 person-years, respectively. After adjusting for conventional cardiovascular risk factors and competing risk of cancer and other causes, carriers with class S allele (L/S or S/S genotypes) had a significantly reduced risk of cardiovascular mortality compared to non-carriers (L/L genotype) [OR, 0.38; 95% CI, 0.16-0.90]. In contrast, no significant association was observed between HO-1 genotype and cancer mortality or mortality from other causes. Shorter (GT)n repeats in the HO-1 gene promoter may confer protective effects against cardiovascular mortality related to arsenic exposure.« less
  • Synthesis and secretion of milk proteins ({alpha}-casein, {beta}-casein, {gamma}-casein, and transferrin) by cultured primary mouse mammary epithelial cells is modulated by the extracellular matrix. In cells grown on released or floating type I collagen gels, mRNA for {beta}-casein and transferrin is increased as much as 30-fold over cells grown on plastic. Induction of {beta}-casein expression depends strongly on the presence of lactogenic hormones, especially prolactin, in the culture. When cells are plated onto partially purified reconstituted basement membrane, dramatic changes in morphology and milk protein gene expression are observed. Cells cultured on the matrix for 6 to 8 d inmore » the presence of prolactin, insulin, and hydrocortisone form hollow spheres and duct-like structures that are completely surrounded by matrix. The cells lining these spheres appear actively secretory and are oriented with their apices facing the lumen. Hybridization experiments indicate that mRNA for {beta}-casein can be increased as much as 70-fold in these cultures. Because > 90% of the cultured cells synthesize immunoreactive {beta}-casein, as compared with only 40% of cells in the late pregnant gland, the matrix appears to be able to induce protein expression in previously silent cells. Synthesis of laminin and assembly of a mammary-specific basal lamina by cells cultured on different extracellular matrices also appears to depend on the presence of lactogenic hormones. These studies provide support for the concept of dynamic reciprocity in which complex interactions between extracellular matrix and the cellular cytoskeleton contribute to the induction and maintenance of tissue-specific gene expression in the mammary gland.« less
  • Detailed molecular definition of the WAGR region at chromosome 11p13 has been achieved by chromosome breakpoint analysis and long-range restriction mapping. Here the authors describe the molecular detection of a cytogenetically invisible 1-megabase deletion in an individual with aniridia, cryptorchidism, and hypospadias but no Wilms tumor (WT). The region of overlap between this deletion and one associated with WT and similar genital anomalies but no aniridia covers a region of 350-400 kilobases, which is coincident with the extent of homozygous deletion detected in tumor tissue from a sporadic WT. A candidate WT gene located within this region has recently beenmore » isolated, suggesting nonpenetrance for tumor expression in the first individual. The inclusion within the overlap region of a gene for WT predisposition and a gene for the best-documented WT-associated genitourinary malformations leads to suggest that both of these anomalies result from a loss-of-function mutation at the same locus. This in turn implies that the WT gene exerts pleiotropic effect on both kidney and genitourinary development, a possibility supported by the observed expression pattern of the WT candidate gene in developing kidney and gonads.« less
  • As an environmental pollutant carbon monoxide (CO) is without equal with regard to ubiquity. Data suggesting adverse effects on the human cardiovascular system associated with CO exposure have engendered concern. In contrast to previous reviewers, our evaluation of the available studies suggests that this concern is largely unwarranted. We found no convincing evidence to support the conclusion that chronic CO exposure increases the risk of developing clinically significant atherosclerotic disease. Acute, low level, Co exposure has been shown to reduce exercise performance. We believe that this effect does not represent a specific toxic action of CO, but is instead amore » consequence of the induced hypoxia. Finally, we conclude that low to moderate level CO exposure does not adversely affect cardiac rhythm in man.« less