Biomedical subjects

M Mark

Publications and source records attributed to M Mark.

At least 55 records · Page 3Linked to original sources

PubMed1999

Cellular retinol-binding protein I is essential for vitamin A homeostasis.

The gene encoding cellular retinol (ROL, vitA)-binding protein type I (CRBPI) has been inactivated. Mutant mice fed a vitA-enriched diet are healthy and fertile. They do not present any of the congenital abnormalities related to retinoic acid (RA) deficiency, indicating that CRBPI is not indispensable for RA synthesis. However, CRBPI deficiency results in an approximately 50% reduction of retinyl ester (RE) accumulation in hepatic stellate cells. This reduction is due to a decreased synthesis and a 6-fold faster turnover, which are not related to changes in the levels of RE metabolizing enzymes, but probably reflect an impaired delivery of ROL to lecithin:retinol acyltransferase. CRBPI-null mice fed a vitA-deficient diet for 5 months fully exhaust their RE stores. Thus, CRBPI is indispensable for efficient RE synthesis and storage, and its absence results in a waste of ROL that is asymptomatic in vitA-sufficient animals, but leads to a severe syndrome of vitA deficiency in animals fed a vitA-deficient diet.

Animals↗

PubMed1999

Essential roles of retinoic acid signaling in interdigital apoptosis and control of BMP-7 expression in mouse autopods.

We previously reported that mice lacking the RARgamma gene and one or both alleles of the RARbeta gene (i.e., RARbeta+/-/RARgamma-/- and RARbeta-/-/RARgamma-/- mutants) display a severe and fully penetrant interdigital webbing (soft tissue syndactyly), caused by the persistence of the fetal interdigital mesenchyme (Ghyselinck et al., 1997, Int. J. Dev. Biol. 41, 425-447). In the present study, these compound mutants were used to investigate the cellular and molecular mechanisms involved in retinoic acid (RA)-dependent formation of the interdigital necrotic zones (INZs). The mutant INZs show a marked decrease in the number of apoptotic cells accompanied by an increase of cell proliferation. This marked decrease was not paralleled by a reduction of the number of macrophages, indicating that the chemotactic cues which normally attract these cells into the INZs were not affected. The expression of a number of genes known to be involved in the establishment of the INZs, the patterning of the autopod, and/or the initiation of apoptosis was also unaffected. These genes included BMP-2, BMP-4, Msx-1, Msx-2, 5' members of Hox complexes, Bcl2, Bax, and p53. In contrast, the mutant INZs displayed a specific, graded, down-regulation of tissue transglutaminase (tTG) promoter activity and of stromelysin-3 expression upon the removal of one or both alleles of the RARbeta gene from the RARgamma null genetic background. As retinoic acid response elements are present in the promoter regions of both tTG and stromelysin-3 genes, we propose that RA might increase the amount of cell death in the INZs through a direct modulation of tTG expression and that it also contributes to the process of tissue remodeling, which accompanies cell death, through an up-regulation of stromelysin-3 expression in the INZs. Approximately 10% of the RARbeta-/- /RARgamma-/- mutants displayed a supernumerary preaxial digit on hindfeet, which is also a feature of the BMP-7 null phenotype (Dudley et al., 1995, Genes Dev. 9, 2795-2807; Luo et al., 1995, Genes Dev. 9, 2808-2820). BMP-7 was globally down-regulated at an early stage in the autopods of these RAR double null mutants, prior to the appearance of the digital rays. Therefore, RA may exert some of its effects on anteroposterior autopod patterning through controlling BMP-7 expression.

Animals↗

PubMed1999

[Quality assurance in the mental health department of the Israel Defense Forces].

A review of quality assurance in the mental health department of the Israel Defence Forces allowed the examination of certain unique elements of quality control which pertain to the military. These include the psychiatric medical board, the computerized documentation of appointments and sessions with soldiers, the psychiatric hospitalization database, control systems implemented in the draft boards, peer-review boards and supervision, and a special officer in charge of handling outside consultations and queries. There were other components of quality assurance and control as well. These instruments are vital in a dynamic system constantly striving to improve clinical performance. Future plans include the continued use and expansion of quality control boards, the inclusion of quality assurance in the curriculum of mental health officers, and the use of clinical guidelines in working with soldiers. All of this is in keeping with the principle of continuous quality improvement, with the aim of viewing the soldier in need of help as a client.

Databases as Topic↗

PubMed1999

Retinoid X receptors are essential for early mouse development and placentogenesis.

Embryos carrying null mutations of both retinoid X receptors alpha and beta (RXRalpha-/-/RXRbeta-/- mutants) were generated. These mutant embryos die between 9.5 and 10.5 days of gestation and display a wide range of abnormalities. The cause of the lethality appears to be the lack of formation of the labyrinthine zone of the chorioallantoic placenta. In a thorough analysis of mutant conceptuses, we establish that RXRs, through heterodimerization with retinoic acid receptors, are essential for postimplantation embryonic development before placentogenesis. RXRs are also essential for the formation of the chorioallantoic placenta, most probably through RXR/peroxisomal proliferator-activated receptor-gamma heterodimers. Interestingly, as a RXR ligand appears dispensable, placentogenesis must be controlled by a yet unknown hormonal ligand(s) activating the heterodimerization partner(s) of RXRs.

Animals↗

PubMed1999

Widespread alterations of alpha-synuclein in multiple system atrophy.

Glial cytoplasmic inclusions (GCI) are the hallmark of multiple system atrophy (MSA), a rare movement disorder frequently associated with autonomic dysfunction. In this study of 21 cases of MSA, GCI were consistently immunoreactive for alpha-synuclein and double-immunostained for ubiquitin and oligodendroglial markers, but not glial fibrillary acidic protein. No statistically significant difference was found in the density of GCI in various brain regions in the two forms of MSA, striatonigral degeneration (SND) and olivopontocerebellar atrophy (OPCA). Postmortem brain samples from 9 cases of MSA were fractionated according to solubility in buffer, Triton-X 100, sodium dodecyl sulfate (SDS), and formic acid, and alpha-synuclein immunoreactivity was measured in Western blots. Total alpha-synuclein immunoreactivity was increased in MSA compared to controls, with no statistically significant difference between SND and OPCA. Most of the increase was due to alpha-synuclein in SDS fractions. In controls this fraction had little or no immunoreactivity. In 7 cases and 4 controls correlations were investigated between quantitative neuropathology and biochemical properties of alpha-synuclein. Surprisingly, the amount of SDS-soluble alpha-synuclein correlated poorly with the number of GCI in adjacent sections. Furthermore, areas with few or no GCI unexpectedly had abundant SDS-soluble alpha-synuclein. These findings provide evidence that modifications of alpha-synuclein in MSA may be more widespread than obvious histopathology. Moreover, these alterations may constitute a biochemical signature for the synucleinopathies.

Aged↗

PubMed1999

Emergence of unusual cytogenetic abnormalities under interferon-alpha therapy in patients with chronic myelogenous leukemia.

New treatments that may change the course of a disease or have potential carcinogenicity can result in the emergence of new cytogenetic or clinical disorders. We report here the cytogenetic evolution of 52 cases of Philadelphia (Ph)-positive myelogenous leukemia (CML) receiving interferon-alpha (IFN-alpha) therapy compared with that of 59 Ph-positive CML cases treated with busulfan (BU) or hydroxyurea (HY). Twenty-one percent of the CML patients receiving IFN-alpha displayed unusual secondary abnormalities, among which alteration of the long arm of chromosome 3, del(7), and del(9) were recurrent. The frequency of these unusual secondary changes was significantly higher than in CML cases after Bu or Hy treatment (P = 0.02). Three of the 11 IFN-alpha-treated CML patients displayed cytogenetic evolution in the chronic phase and, in two cases, the cytogenetic findings were transient, inasmuch as they disappeared upon withdrawal of IFN-alpha. In addition, a majority of cytogenetic abnormalities involved chromosome 3 at bands 3q21 and 3q26, which corresponds to the locus of EVI1, a gene implicated in the development or progression of human myeloid leukemias. Possible explanations include: toxicity of IFN-alpha by effect on bone marrow stroma, immune-modulating effects of IFN-alpha, and mutagenic effects of IFN-alpha. The mechanisms underlying these cytogenetic changes remain to be elucidated. However, our data suggest that IFN-alpha induces additional cytogenetic abnormalities even in the chronic phase through its immune-modulating effects and that these unusual cytogenetic abnormalities do not alter the history of CML.

Adolescent↗

PubMed1999

A genetic dissection of the retinoid signalling pathway in the mouse.

To determine the functions of retinoic acid receptors RAR and RXR, we have systematically knocked-out their genes by homologous recombination in the embryonic stem cells and generated null-mutant mice. This approach has allowed us to perform a genetic dissection of the retinoic acid signalling pathway.

Animals↗

PubMed1999

Quetiapine as an alternative to clozapine in the treatment of dopamimetic psychosis in patients with Parkinson's disease.

There are many difficulties associated with the late stages of Parkinson's disease (PD), but psychosis and agitation may be the most disturbing for both patients and care givers, and often precipitate the pivotal decision for long-term nursing home placement. While the addition of antipsychotic drugs or the withdrawal of antiparkinsonian drugs may improve the behavioral problem, these strategies usually worsen the motor difficulties. Clozapine has been studied in PD for over a decade, and while it appears to be effective, there are safety and tolerability concerns associated with it. In addition, in New Jersey, Medicaid no longer pays for the home blood draws that are required for home-bound patients. This led to a situation in which we had patients who needed to stop clozapine and begin an alternative therapy. Because quetiapine seems particularly well suited to patients with PD based on in vitro and in vivo studies we have begun to try this medication in PD patients who need to stop clozapine. This article reports three case histories of patients with PD, confusion and dopamimetic psychosis who had been previously managed with clozapine and who were successfully switched to quetiapine. At doses from 12.5 to 150 mg/day quetiapine was well tolerated, resulting in behavioral improvement and no real increase in parkinsonism. These case histories raise the possibility that quetiapine may represent a viable alternative to clozapine in PD patients with dopamimetic psychosis and behavioral disturbances.

Aged↗

PubMed1999

Influence of nitrovasodilators and endothelin-1 on rheology of human blood in vitro.

1. The shear stress of flowing blood profoundly influences the release of endothelium-dependent vasodilative and constrictive factors. Conversely, the influence of these mediators such as nitric oxide (NO) or endothelin-1 (ET-1) on blood rheology remains elusive. In the present study the influence of nitrovasodilators and ET-1 on red blood cell (RBC) shape and whole blood viscosity were investigated. 2. Incubation of whole blood with sodium-nitroprusside (SNP, 10-5 - 10-2 M), glyceryl trinitrate (GTN, 0.0001 - 0.1 mg mL-1), S-nitroso-N-acetylpenicillamine (SNAP, 10-6 - 10-3 M), and the active metabolite of molsidomine (SIN-1, 10-6 - 10-3 M), but not molsidomine (10-6 - 10-3 M), resulted in significantly increased amounts of methaemoglobin, indicating a relevant interaction with RBCs. Treatment with SNP at 10-2 M induced a marked echinocytosis (morphological index: 2.23+/-0.98 vs -0.17+/-0.10; P<0.001) and increased blood viscosity (haematocrit 45%) at a high shear rate of 94.5 s-1 (6.46+/-0.60 vs 5.07+/-0.35 mPa.s; P<0.01) and a low shear rate of 0.1 s-1 (88.6+/-36.8 vs 42.1+/-11.7 mPa.s; P<0.01). Echinocytosis was probably due to cyanide accumulation. SIN-1 at 10-3 M slightly decreased high shear viscosity (4.88+/-0.28 vs 4. 95+/-0.30 mPa.s; P<0.05). SNAP at 10-3 M slightly increased both high (5.14+/-0.23 vs 5.05+/-0.24 mPa.s; P<0.01) and low shear (53.9+/-7.2 vs 51.2+/-5.9 mPa.s; P<0.05) viscosity. Molsidomine and GTN failed to influence whole blood viscosity. ET-1 (10-9 - 10-6 M) had no effect on RBC shape and viscosity. 3. We conclude that the most important modulators of vascular tone, NO and ET-1, do not affect RBC shape and blood viscosity, which is important from both a physiological and a pharmacological point of view.

Adult↗

PubMed1999

Risk factors for violence among long-stay psychiatric patients: national study.

This study identified risk factors for violence among long-stay (1 year or more) psychiatric patients in Israel (n = 2946) using data from a national reevaluation of such patients. Patients were rated as being violent if hospital staff or patient charts indicated an incident of physical violence at least every few months. The relationship between violence and patients' functioning, living conditions, treatment, background and hospitalization history was studied. In total, 22.8% of patients were violent. Based on logistic regression analysis, the risk factors for being violent were younger age, younger age at first hospitalization, poorer self-care, having more frequent visitors, and the patient not having his or her own clothing. The data for age and lack of gender differences confirm previous findings. However, the results regarding clothing, visitors, poor self-care and age of onset are unique. The results of this study suggest that the violent behaviour of in-patients is related to both individual and environmental variables.

Adolescent↗

PubMed1999

Behavioral and intellectual markers for schizophrenia in apparently healthy male adolescents.

OBJECTIVE: Subtle behavioral and intellectual abnormalities are often present in apparently healthy adolescents who later develop schizophrenia. The authors investigated whether these abnormalities can predict vulnerability for schizophrenia before the first psychotic manifestation. METHOD: The study consisted of linking the Israeli Draft Board Registry with the National Psychiatric Hospitalization Case Registry. The draft board tests measure intelligence, social functioning, organizational ability, interest in physical activity, and individual autonomy. Patients (N = 509) were compared to nonpatients, i.e., adolescents not appearing in the National Psychiatric Registry (N = 9,215), matched to patients by age, gender, and school attended at time of testing. RESULTS: Healthy male adolescents who were later hospitalized for schizophrenia had significantly lower test scores on all measures than adolescents not reported to the National Psychiatric Registry. The strongest predictors for schizophrenia were deficits in social functioning, organizational ability, and intellectual functioning. When patients were compared to matched nonpatients, the prediction model had a 75% sensitivity, a 100% specificity, a positive predictive value of 72%, and an overall rate of correct classification of 87.5%. Applied to the Israeli Draft Board Registry, the model yielded a sensitivity of 74.7%, a validated specificity of 99.7%, and a positive predictive value of 42.7%. CONCLUSIONS: This study demonstrated that simple assessment tools can predict predisposition to schizophrenia in healthy male adolescents. The model's predictive ability does not change as a function of the time elapsed between testing and first hospitalization. This suggests that the model identifies apparently healthy individuals who will manifest the disease later who are not prodromal to psychosis. Easily applied tools allowing early identification of schizophrenia or vulnerability to it may enable early intervention.

Adolescent↗

PubMed1999

Synergistic activities of alpha3 and alpha6 integrins are required during apical ectodermal ridge formation and organogenesis in the mouse.

Integrins alpha6beta1 and alpha6beta4 are cell surface receptors for laminins. Integrin alpha6-null mice die at birth with severe skin blistering and defects in the cerebral cortex and in the retina. Integrin alpha3beta1 can associate with laminins and other ligands. Integrin alpha3-null mice also die at birth, with kidney and lung defects at late stages of development, and moderate skin blistering. To investigate possible overlapping functions between alpha3 and alpha6 integrins, we analyzed the phenotype of compound alpha3-/-/alpha6-/- mutant embryos. Double homozygous mutant embryos were growth-retarded and displayed several developmental defects not observed in the single mutant animals. First, limb abnormalities characterized by an absence of digit separation and the fusion of preskeletal elements were observed. Further analyses indicated a defect in the apical ectodermal ridge, an essential limb organizing center. In the double mutant, the ridge appeared flattened, and ridge cells did not show a columnar morphology. A strong reduction in ridge cell proliferation and alterations of the basal lamina underlying the ectoderm were observed. These results suggest that alpha3 and alpha6 integrins are required for the organization or compaction of presumptive apical ectodermal ridge cells into a distinct differentiated structure. Additional defects were present: an absence of neural tube closure, bilateral lung hypoplasia, and several abnormalities in the urogenital tract. Finally, an aggravation of brain and eye lamination defects was observed. The presence of novel phenotypes in double mutant embryos demonstrates the synergism between alpha3 and alpha6 integrins and their essential roles in multiple processes during embryogenesis.

Abnormalities, Multiple↗

PubMed1999

Key roles of retinoic acid receptors alpha and beta in the patterning of the caudal hindbrain, pharyngeal arches and otocyst in the mouse.

Mouse fetuses carrying targeted inactivations of both the RAR(&agr;) and the RARbeta genes display a variety of malformations in structures known to be partially derived from the mesenchymal neural crest originating from post-otic rhombomeres (e.g. thymus and great cephalic arteries) (Ghyselinck, N., Dupé, V., Dierich, A., Messaddeq, N., Garnier, J.M., Rochette-Egly, C., Chambon, P. and Mark M. (1997). Int. J. Dev. Biol. 41, 425-447). In a search for neural crest defects, we have analysed the rhombomeres, cranial nerves and pharyngeal arches of these double null mutants at early embryonic stages. The mutant post-otic cranial nerves are disorganized, indicating that RARs are involved in the patterning of structures derived from neurogenic neural crest, even though the lack of RARalpha and RARbeta has no detectable effect on the number and migration path of neural crest cells. Interestingly, the double null mutation impairs early developmental processes known to be independent of the neural crest e.g., the initial formation of the 3rd and 4th branchial pouches and of the 3rd, 4th and 6th arch arteries. The double mutation also results in an enlargement of rhombomere 5, which is likely to be responsible for the induction of supernumerary otic vesicles, in a disappearance of the rhombomere 5/6 boundary, and in profound alterations of rhombomere identities. In the mutant hindbrain, the expression domain of kreisler is twice its normal size and the caudal stripe of Krox-20 extends into the presumptive rhombomeres 6 and 7 region. In this region, Hoxb-1 is ectopically expressed, Hoxb-3 is ectopically up-regulated and Hoxd-4 expression is abolished. These data, which indicate that retinoic acid signaling through RARalpha and/or RARbeta is essential for the specification of rhombomere identities and for the control of caudal hindbrain segmentation by restricting the expression domains of kreisler and of Krox-20, also strongly suggest that this signaling plays a crucial role in the posteriorization of the hindbrain neurectoderm.

Animals↗

PubMed1999

Beta-cell gene expression and functional characterisation of the human insulinoma cell line CM.

Animal insulinoma cell lines are widely used to study physiological and pathophysiological mechanisms involved in glucose metabolism and to establish in vitro models for studies on beta-cells. In contrast, human insulinoma cell lines are rarely used because of difficulties in obtaining and culturing them for long periods. The aim of our study was to investigate, under different experimental conditions, the capacity of the human insulinoma cell line CM to retain beta-cell function, particularly the expression of constitutive beta-cell genes (insulin, the glucose transporters GLUT1 and GLUT2, glucokinase), intracellular and secreted insulin, beta-cell granules, and cAMP content. Results showed that CM cells from an early-passage express specific beta-cell genes in response to glucose stimulation, in particular the insulin and GLUT genes. Such capacity is lost at later passages when cells are cultured at standard glucose concentrations. However, if cultured at lower glucose concentration (0.8 mM) for a longer time, CM cells re-acquire the capacity to respond to glucose stimulation, as shown by the increased expression of beta-cell genes (insulin, GLUT2, glucokinase). Nonetheless, insulin secretion could not be restored under such experimental conditions despite the presence of intracellular insulin, although cAMP response to a potent activator of adenylate cyclase, forskolin, was present indicating a viable system. In conclusion, these data show that the human insulinoma cell line CM, at both early-passage and late-passage, posseses a functional glucose-signalling pathway and insulin mRNA expression similar to normal beta-cells, representing, therefore, a good model for studies concerning the signalling and expression of beta-cells. Furthermore, we have previously shown that it is also a good model for immunological studies. In this respect it is important to note that the CM cell line is one of the very few existing human beta-cell lines in long-term culture.

Adenylyl Cyclases↗

PubMed1999

[Clozapine in the treatment of schizophrenia].

Schizophrenia is associated with brain abnormalities and is typically evidenced by disorganized speech and behavior, delusions, and hallucinations; it usually requires extended hospitalization. Its incidence in the western world is estimated at 4-7 cases/10,000/year. A method of shortening hospitalization and improving level of functioning is the use of unique medication, including clozapine, which has been in use in Israel for the past 6 years. We report 327 patients who participated in a community rehabilitation program and were treated with clozapine. They were compared with 417 patients who corresponded to the guidelines of the Director of Mental Health Services for treatment with clozapine, but were not treated with it for reasons not defined in the guidelines. The study included those 25-44 and 45-64 years of age and according to the division of the population of patients hospitalized in both government and private hospitals. The project demonstrates the savings from use of clozapine as opposed to the alternative of hospitalizing these patients. It also shows the complexity and difficulty in assimilating new technologies, in relation to the influence of social considerations and supplier/insurer accounting on the patterns of technological assimilation.

Adult↗

PubMed1998

Repaglinide and related hypoglycemic benzoic acid derivatives.

The structure-activity relationships in two series of hypoglycemic benzoic acid derivatives (5, 6) were investigated. Series 5 resulted from meglitinide (3) when the 2-methoxy was replaced by an alkyleneimino residue. Maximum activity was observed with the cis-3, 5-dimethyl-piperidino (5h) and the octamethyleneimino (5l) residues. Series 6 resulted from the meglitinide analogon 4 bearing an inversed amido function when the 2-methoxy, the 5-fluoro, and the alpha-methyl residue were replaced by a 2-piperidino, a 5-hydrogen, and a larger alpha-alkyl residue, respectively. An alkoxy residue ortho to the carboxy group further increased activity and duration of action in the rat. The most active racemic compound, 6al (R4 = isobutyl; R = ethoxy), turned out to be 12 times more active than the sulfonylurea (SU) glibenclamide (1). Activity was found to reside predominantly in the (S)-enantiomers. Compared with the SUs 1 and 2 (glimepiride), the most active enantiomer, (S)-6al (AG-EE 623 ZW; repaglinide; ED50 = 10 micro/kg po), is 25 and 18 times more active. Repaglinide turned out to be a useful therapeutic for type 2 diabetic patients; approval was granted recently by the FDA and the EMEA. From investigations on the pharmacophoric groups in compounds of type 5 and 6, it was concluded that in addition to the two already known-the acidic group (COOH; SO2NH) and the amidic spacer (CONH; NHCO)-the ortho residue R1 (alkyleneimino; alkoxy; oxo) must be regarded as a third one. A general pharmacophore model suitable for hypoglycemic benzoic acid derivatives, SUs, and sulfonamides is proposed (Figure 6). Furthermore, from superpositions of low-energy conformations (LECs) of 1, 2, and (S)-6al, it was concluded that a common binding conformation (LEC II; Figure 10B) may exist and that differences in binding to the SU receptor and in the mechanism of insulin release between repaglinide and the two SUs may be due to specific hydrophobic differences.

ATP-Binding Cassette Transporters↗

PubMed1998

Essential role of alpha 6 integrins in cortical and retinal lamination.

Extracellular matrix (ECM) is believed to play important roles in many aspects of nervous system development [1]. The laminins are ECM glycoproteins expressed in neural tissues and are potent stimulators of neurite outgrowth in vitro [1-3]. Genetic approaches using Drosophila and Caenorhabditis elegans have demonstrated a role for laminin and a laminin receptor in vivo in axon pathfinding and fasciculation, respectively [4,5]. In higher organisms, however, the role of laminins in the development of the nervous system is poorly understood. Integrins alpha 6 beta 1 and alpha 6 beta 4 are major laminin receptors. A role for the alpha 6 integrin in neurulation has been reported in amphibians [6]. We previously described mice lacking integrin alpha 6; these mice died at birth with severe skin blistering [7]. Detailed analyses of integrin alpha 6-/- mice reported here revealed abnormalities in the laminar organization of the developing cerebral cortex and retina. Ectopic neuroblastic outgrowths were found on the brain surface and in the vitreous body in the eye. Alterations of laminin deposition were found in mutant brains. Thus, this study provides evidence for an essential role of integrin-laminin interactions in the proper development of the nervous system. These observations are particularly significant given the recent report that human patients suffering from epidermolysis bullosa can carry mutations in ITGA6, the gene encoding the alpha 6 integrin chain [8,9].

Animals↗

PubMed1998

Contribution of retinoic acid receptor beta isoforms to the formation of the conotruncal septum of the embryonic heart.

To investigate the relative contribution of retinoic acid receptor (RAR)beta isoforms in conotruncal septation, RAR beta 1 and beta 3 were inactivated in the mouse. Mice lacking RAR beta 1 and beta 3 appear normal. Disruption of these isoforms in RAR alpha or RAR gamma null genetic backgrounds results in a high postpartum lethality. However, except for ocular defects found in RAR beta 1-3/RAR gamma compound mutants, the double null mutants display only abnormalities seen in single null mutants. This probably reflects a functional redundancy with other RARs, most notably with RAR beta 2 which is five- to sixfold more abundant than RAR beta 1 and beta 3 and whose domain of expression is largely overlapping. The conotruncal ridges form normally in retinoid X receptor (RXR)alpha/RAR beta compound mutants but fail to fuse, apparently as a result of excessive apoptosis of mesenchymal cells. Additionally, many cardiomyocytes in the conotruncal wall of these mutants appear necrotic. Although RAR beta 1 and beta 3 are expressed specifically in the conotruncal ridges, failure of fusion of these structures is not more frequent in RXR alpha/RAR beta 1-3 double null mutants than in RXR alpha single null mutants. Similarly, the disruption of the sole RAR beta 2 isoform in a RXR alpha null genetic background does not result in an increase of the frequency of conotruncal septum agenesis. However, this agenesis is fully penetrant in RXR alpha/RAR beta +/- mutants, which reflects distinct role of RXR alpha:RAR beta 1 (and beta 3) and RXR alpha:RAR beta 2 heterodimers in promoting the survival of conotruncal mesenchymal cells. Unexpectedly, we discovered that, in wild-type embryos, the conotruncal mesenchyme is a major site of morphogenetic cell death and that conotruncal myocytes are occasionally necrotic. Thus, excessive cell death in the conotruncus is a potential cause of ventricular septal defects in humans.

Animals↗