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C Mendelsohn

Publications and source records attributed to C Mendelsohn.

At least 19 recordsLinked to original sources
PubMed2001

IRTA1 and IRTA2, novel immunoglobulin superfamily receptors expressed in B cells and involved in chromosome 1q21 abnormalities in B cell malignancy.

Abnormalities of chromosome 1q21 are common in B cell malignancies, but their target genes are largely unknown. By cloning the breakpoints of a (1;14) (q21;q32) chromosomal translocation in a myeloma cell line, we have identified two novel genes, IRTA1 and IRTA2, encoding cell surface receptors homologous to the Fc and inhibitory receptor families. Both genes are selectively expressed in mature B cells: IRTA1 in marginal zone B cells and IRTA2 in centrocytes, marginal zone B cells, and immunoblasts. As a result of the t(1;14), IRTA1 is fused to the immunoglobulin Calpha domain to produce a chimeric IRTA1/Calpha fusion protein. In tumor cell lines with 1q21 abnormalities, IRTA2 expression is deregulated. Thus, IRTA1 and IRTA2 are novel immunoreceptors implicated in B cell development and lymphomagenesis.

Amino Acid Sequence↗
PubMed2001

Vitamin A controls epithelial/mesenchymal interactions through Ret expression.

Mutations or rearrangements in the gene encoding the receptor tyrosine kinase RET result in Hirschsprung disease, cancer and renal malformations. The standard model of renal development involves reciprocal signaling between the ureteric bud epithelium, inducing metanephric mesenchyme to differentiate into nephrons, and metanephric mesenchyme, inducing the ureteric bud to grow and branch. RET and GDNF (a RET ligand) are essential mediators of these epithelial-mesenchymal interactions. Vitamin A deficiency has been associated with widespread embryonic abnormalities, including renal malformations. The vitamin A signal is transduced by nuclear retinoic acid receptors (RARs). We previously showed that two RAR genes, Rara and Rarb2, were colocalized in stromal mesenchyme, a third renal cell type, where their deletion led to altered stromal cell patterning, impaired ureteric bud growth and downregulation of Ret in the ureteric bud. Here we demonstrate that forced expression of Ret in mice deficient for both Rara and Rarb2 (Rara(-/-)Rarb2(-/-)) genetically rescues renal development, restoring ureteric bud growth and stromal cell patterning. Our studies indicate the presence of a new reciprocal signaling loop between the ureteric bud epithelium and the stromal mesenchyme, dependent on Ret and vitamin A. In the first part of the loop, vitamin-A-dependent signals secreted by stromal cells control Ret expression in the ureteric bud. In the second part of the loop, ureteric bud signals dependent on Ret control stromal cell patterning.

Animals↗
PubMed2000

Regulation of retinoic acid signaling during lung morphogenesis.

Little is known about how retinoic acid (RA) synthesis, utilization and metabolism are regulated in the embryonic lung and how these activities relate to lung pattern formation. Here we report that early lung bud formation and subsequent branching morphogenesis are characterized by distinct stages of RA signaling. At the onset of lung development RA signaling is ubiquitously activated in primary buds, as shown by expression of the major RA-synthesizing enzyme, RALDH-2 and activation of a RARE-lacZ transgene. Nevertheless, further airway branching appears to require downregulation of RA pathways by decreased synthesis, increased RA degradation in the epithelium via P450RAI-mediated metabolism, and inhibition of RA signaling in the mesenchyme by COUPTF-II expression. These mechanisms controlling local RA signaling may be critical for normal branching, since we show that manipulating RA levels in vitro to maintain RA signaling activated as in the initial stage, leads to an immature lung phenotype characterized by failure to form typical distal buds. We show that this phenotype likely results from RA interfering with the establishment of a distal signaling center, altering levels and distribution of Fgf10 and Bmp4, genes that are essential for distal lung formation. Furthermore, RA upregulates P450RAI expression, suggesting the presence of feedback mechanisms controlling RA availability. Our study illustrates the importance of regional mechanisms that control RA availability and utilization for correct expression of pattern regulators and normal morphogenesis during lung development.

Aldehyde Oxidoreductases↗
PubMed1999

The targeted disruption of both alleles of RARbeta(2) in F9 cells results in the loss of retinoic acid-associated growth arrest.

F9 teratocarcinoma cell lines, carrying one or two disrupted alleles of the RARbeta(2) gene, were generated by homologous recombination to study the role of RARbeta(2) in mediating the effects of retinoids on cell growth and differentiation. Retinoic acid (RA) does not induce growth arrest of the RARbeta(2)-/- cells, whereas the F9 WT and RARbeta(2)+/- heterozygote lines undergo RA-induced growth arrest. The RARbeta(2)+/- lines also exhibit a faster cell cycle transit time in the absence of RA. The RARbeta(2)-/- stem cells exhibit an altered morphology when compared with the F9 WT parent line, and after RA treatment, the RARbeta(2)-/- cells do not exhibit a fully differentiated cell morphology. As compared with F9 WT cells, the RARbeta-/- cells exhibited a markedly lower induction of several early RA-responsive genes and no induction of laminin B1, a late response gene. The induction of RA metabolism in the F9 RARbeta(2)-/- cells following differentiation was not impaired. The research presented here, and prior research suggest that RARbeta is required for RA-induced growth arrest in a variety of cell types and that RARbeta also functions in mediating late responses to RA. These findings are significant in view of the reduced expression of RARbeta transcripts in a number of different types of human carcinomas.

Alleles↗
PubMed1999

Stromal cells mediate retinoid-dependent functions essential for renal development.

The essential role of vitamin A and its metabolites, retinoids, in kidney development has been demonstrated in vitamin A deficiency and gene targeting studies. Retinoids signal via nuclear transcription factors belonging to the retinoic acid receptor (RAR) and retinoid X receptor (RXR) families. Inactivation of RARaplpha and RARbeta2 receptors together, but not singly, resulted in renal malformations, suggesting that within a given renal cell type, their concerted function is required for renal morphogenesis. At birth, RARalpha beta2(-) mutants displayed small kidneys, containing few ureteric bud branches, reduced numbers of nephrons and lacking the nephrogenic zone where new nephrons are continuously added. These observations have prompted us to investigate the role of RARalpha and RARbeta2 in renal development in detail. We have found that within the embryonic kidney, RARalpha and RARbeta2 are colocalized in stromal cells, but not in other renal cell types, suggesting that stromal cells mediate retinoid-dependent functions essential for renal development. Analysis of RARalpha beta2(-) mutant kidneys at embryonic stages revealed that nephrons were formed and revealed no changes in the intensity or distribution of molecular markers specific for different metanephric mesenchymal cell types. In contrast the development of the collecting duct system was greatly impaired in RARalpha beta2(-) mutant kidneys. Fewer ureteric bud branches were present, and ureteric bud ends were positioned abnormally, at a distance from the renal capsule. Analysis of genes important for ureteric bud morphogenesis revealed that the proto-oncogene c-ret was downregulated. Our results suggest that RARalpha and RARbeta2 are required for generating stromal cell signals that maintain c-ret expression in the embryonic kidney. Since c-ret signaling is required for ureteric bud morphogenesis, loss of c-ret expression is a likely cause of impaired ureteric bud branching in RARalpha beta2(-) mutants.

Animals↗
PubMed1997

The risk of venous thromboembolism in the orthopedic patient: epidemiological and physiological data.

Venous thromboembolism is responsible for 500,000 deaths annually in industrialized countries. It is probably the most common preventable cause of death in elective orthopedic surgery patients. Rates of deep vein thrombosis (DVT) and fatal pulmonary embolism (PE) in unprotected orthopedic patient populations are high. The overall DVT rate is > 40% in patients undergoing hip or knee arthroplasty or suffering from multiple injuries. The proximal DVT rate for these patients is > or = 15%, and the fatal PE rate is > or = 1%. Risk factors associated with venous thromboembolism are related to the vascular injury, activation of blood coagulation, and venous stasis. Lower extremity orthopedic procedures carry a risk greater than that of surgery itself. Thus, orthopedic patients are at high risk for venous thromboembolic conditions. A systematic assessment of this risk should be performed in every patient, and an appropriate management plan should be implemented.

Humans↗
PubMed1995

Developmental roles of the retinoic acid receptors.

Retinoic acid, one of the principle active metabolites of vitamin A (retinol), is believed to be essential for numerous developmental and physiological processes. Vitamin A deprivation (VAD) during development leads to numerous congenital defects. Previous studies of retinoic acid receptor (RAR) deficient mice failed to reveal any of these VAD-induced defects. This finding suggested that either the RARs are functionally redundant or that they are not critically required during development. In order to address these possibilities, we derived a number of RAR compound mutants. Unlike RAR single mutants, these compound null mutants died either in utero or shortly following birth. Histological analysis revealed essentially all of the defects characteristic of fetal VAD. A number of additional malformations, not described in previous VAD studies, were also observed. These included defects of the ocular and salivary glands and their ducts, the skeletal elements of the fore- and hindlimbs, and the cervical region of the axial skeleton. In addition, with the exception of derivatives forming within the first pharyngeal arch, most of the elements derived from mesectoderm emanating from cranial and hindbrain levels were affected. A number of these mutants also exhibited supernumerary cranial skeletal elements characteristics of the reptilian skull. A summary of the defects found in these RAR double mutants is presented.

Animals↗
PubMed1995

Roles of retinoic acid receptors and of Hox genes in the patterning of the teeth and of the jaw skeleton.

Retinoic acid receptors and transcriptional factors encoded by Hox genes play key roles in vertebrate development and belong to an integrated functional network. To investigate the actual functions of these molecules during ontogenesis and in particular in the patterning of the cranial neural crest cells giving rise to the teeth and to the jaw bones, we have generated null mutant mice lacking functional retinoic acid receptors or Hox genes by gene targeting in embryonic stem cells.

Animals↗
PubMed1994

Retinoic acid receptor beta 2 (RAR beta 2) null mutant mice appear normal.

Vertebrates are highly sensitive to both retinoic acid (RA) deficiency and excess. The RA signal is thought to be transduced by nuclear receptors (the RAR and RXR families) which activate the expression of target genes via cis-acting transcriptional enhancer elements. Each of the three RAR genes, RAR alpha, RAR beta, and RAR gamma, gives rise to several isoforms by differential usage of two promoters and alternative splicing. RAR beta 2 is the most abundant of the four RAR beta isoforms, and its transcription is spatially and temporally restricted in developing embryos, suggesting that it might perform specific functions. Furthermore, RAR beta 2 expression can be induced via a retinoic acid response element located in its promoter region. This RA effect is particularly interesting since under conditions of RA excess, RAR beta 2 promoter activity and transcript accumulation are induced in regions of developing embryos in which malformations subsequently appear, such as the craniofacial region, the hindbrain, and the limbs. These findings have led to the suggestion that the RAR beta 2 isoform might mediate some of the teratogenic effects of RA. In this study, we have eliminated RAR beta 2 expression by targeted gene disruption. RAR beta 2 null mutants exhibit an apparently normal phenotype, indicating that other RARs must compensate for RAR beta 2 sufficiently well to allow normal prenatal and postnatal development to proceed. By challenging RAR beta 2 null embryos with teratogenic doses of RA, we have also directly addressed the question of whether RAR beta 2 is required for mediating RA-induced malformations.

Animals↗
PubMed1994

RAR beta isoforms: distinct transcriptional control by retinoic acid and specific spatial patterns of promoter activity during mouse embryonic development.

That both deficiency and excess of vitamin A lead to a wide spectrum of congenital abnormalities has strongly implicated the active metabolite, retinoic acid (RA), in normal embryonic development. There are 3 families of RA receptors (RARs), RAR alpha, RAR beta and RAR gamma, each having at least two isoforms derived from primary transcripts initiated at two promoters P1 and P2 (reviewed in Leid et al., 1992) Transcripts encoding all 4 isoforms of RAR beta (RAR beta 1 to RAR beta 4) accumulate in embryonal carcinoma (EC) cells in the presence of RA. It has been previously shown that the RA modulation of RAR beta 2/beta 4 transcripts is achieved at the level of transcriptional initiation via a RA response element (RARE) present in the P2 RAR beta 2/beta 4 promoter. In contrast, the mechanism by which RA up-regulates RAR beta 1/beta 3 transcripts has not yet been elucidated. We describe here the isolation of the P1 RAR beta 1/beta 3 promoter and characterization of its activity in transgenic animals. We find that RAR beta 1/beta 3 promoter activity, which is apparently confined to the embryonic CNS, is not modified by RA treatment, unlike that of the RAR beta 2/beta 4 promoter (Mendelsohn et al., 1991). Nuclear run-on transcription analysis in EC cells supports the conclusion that RAR beta 1/beta 3 transcript initiation is not modulated by RA, and that the RA-induced accumulation of RAR beta 1/beta 3 transcripts occur via a RA-dependent release of a block in RNA chain elongation.

Animals↗
PubMed1994

Function of the retinoic acid receptors (RARs) during development (I). Craniofacial and skeletal abnormalities in RAR double mutants.

Numerous congenital malformations have been observed in fetuses of vitamin A-deficient (VAD) dams [Wilson, J. G., Roth, C. B., Warkany, J., (1953), Am. J. Anat. 92, 189-217]. Previous studies of retinoic acid receptor (RAR) mutant mice have not revealed any of these malformations [Li, E., Sucov, H. M., Lee, K.-F., Evans, R. M., Jaenisch, R. (1993) Proc. Natl. Acad. Sci. USA 90, 1590-1594; Lohnes, D., Kastner, P., Dierich, A., Mark, M., LeMeur, M., Chambon, P. (1993) Cell 73, 643-658; Lufkin, T., Lohnes, D., Mark, M., Dierich, A., Gorry, P., Gaub, M. P., Lemeur, M., Chambon, P. (1993) Proc. Natl. Acad. Sci. USA 90, 7225-7229; Mendelsohn, C., Mark, M., Dollé, P., Dierich, A., Gaub, M.P., Krust, A., Lampron, C., Chambon, P. (1994a) Dev. Biol. in press], suggesting either that there is a considerable functional redundancy among members of the RAR family during ontogenesis or that the RARs are not essential transducers of the retinoid signal in vivo. In order to discriminate between these possibilities, we have generated a series of RAR compound null mutants. These RAR double mutants invariably died either in utero or shortly after birth and presented a number of congenital abnormalities, which are reported in this and in the accompanying study. We describe here multiple eye abnormalities which are found in various RAR double mutant fetuses and are similar to those previously seen in VAD fetuses. Interestingly, we found further abnormalities not previously reported in VAD fetuses.(ABSTRACT TRUNCATED AT 250 WORDS)

Abnormalities, Multiple↗
PubMed1994

Function of the retinoic acid receptors (RARs) during development (II). Multiple abnormalities at various stages of organogenesis in RAR double mutants.

Compound null mutations of retinoic acid receptor (RAR) genes lead to lethality in utero or shortly after birth and to numerous developmental abnormalities. In the accompanying paper (Lohnes, D., Mark., M., Mendelsohn, C., Dollé, P., Dierich, A., Gorry, Ph., Gansmuller, A. and Chambon, P. (1994). Development 120, 2723-2748), we describe malformations of the head, vertebrae and limbs which, with the notable exception of the eye defects, were not observed in the offspring of vitamin A-deficient (VAD) dams. We report here abnormalities in the neck, trunk and abdominal regions of RAR double mutant mice, which include: (i) the entire respiratory tract, (ii) the heart, its outlow tract and the great vessels located near the heart, (iii) the thymus, thyroid and parathyroid glands, (iv) the diaphragm, (v) the genito-urinary system, and (vi) the lower digestive tract. A majority of these abnormalities recapitulate those observed in the fetal VAD syndrome described by Joseph Warkany's group more than fourty years ago [Wilson, J. G., Roth, C. B. and Warkany, J. (1953) Am. J. Anat., 92, 189-217; and refs therein]. Our results clearly demonstrate that RARs are essential for vertebrate ontogenesis and therefore that retinoic acid is the active retinoid, which is required at several stages of the development of numerous tissues and organs. We discuss several possibilities that may account for the apparent functional redundancy observed amongst retinoic acid receptors during embryogenesis.

Abnormalities, Multiple↗
PubMed1993

Retinoic acid signal transduction pathways.

Complexity in the retinoid signaling system arises from a combination of several forms of retinoic acid which possess differential activities, multiple cytoplasmic binding proteins and nuclear receptors that have distinct ligand specificities and functional properties, and the existence of polymorphic retinoic acid response elements. Additional diversity appears to be generated by heterodimeric interactions between the two classes of nuclear retinoic acid receptors and between retinoic acid receptors and some other members of the nuclear receptor superfamily. Thus, a complex array of combinatorial effects is beginning to emerge that may account for the pleiotropic effects of retinoids.

Amino Acid Sequence↗
PubMed1992

Retinoid receptors in vertebrate limb development.

Although the precise role of retinoids in limb development remains obscure, the finding that retinoic acid can produce major alterations in limb patterning suggests that this ligand might be involved in the process of limb morphogenesis. Here we describe the patterns of expression of retinoic acid receptors and cytosolic retinoid binding proteins during the course of limb morphogenesis. Examining the distribution of these molecules in the limb and correlating their presence with important processes in limb development could help elucidate their possible functions.

Animals↗
PubMed1992

Retinoid receptors and binding proteins.

Retinoids, in particular all-trans retinoic acid (T-RA), are essential for normal development and homeostasis of vertebrates. Although many effects of retinoids, particularly with regard to teratogenicity, have been described in the literature, the mechanisms by which these simple signalling molecules work has only recently begun to be elucidated. We now recognize at least two classes of retinoid-binding proteins and two families of retinoid receptors. The ultimate interpretation of the retinoid signal within a given cell is probably the result of a complex series of interactions between these proteins, yet little is understood concerning the role each member of this signalling pathway plays. It is therefore imperative to dissect the molecular mechanisms which transduce the effects of these ligands, both in vivo and in isolated systems. One approach we are employing is gene targeting of retinoic acid receptors (RARs) and cellular retinoid-binding proteins to generate mice in which one or more of these genes has been functionally inactivated.

Animals↗
PubMed1991

Multiple isoforms of the mouse retinoic acid receptor alpha are generated by alternative splicing and differential induction by retinoic acid.

Together with the previously described mouse retinoic acid receptor alpha-1 (mRAR-alpha 1, formerly mRAR-alpha 0), we have isolated and characterized here a total of seven mRAR-alpha cDNA isoforms (mRAR-alpha 1 to alpha 7). These isoforms are generated from mRAR-alpha primary transcript(s) of a single gene by alternative splicing of at least eight different exons with the exon which encodes the amino acid sequence of their common B region. All of these isoforms differ in their 5'-untranslated regions (5'-UTRs) and, in the case of mRAR-alpha 1 and alpha 2, also in the sequences encoding the N-terminal A region which is known to be important for differential trans-activation by other members of the nuclear receptor superfamily. In addition, the sequences encoding the open reading frames (ORFs) of mRAR-alpha 3 and alpha 4 cDNA isoforms remain open to their very 5' ends, which suggests that these two isoforms may also encode RAR-alpha s with unique A region amino acid sequences. The two predominant isoforms, mRAR-alpha 1 and alpha 2, were found to be differentially expressed in mouse adult and fetal tissues, as well as in P19 and F9 embryonal carcinoma (EC) cell lines. Interestingly, the expression of mRAR-alpha 2, in contrast to that of the mRAR-alpha 1 isoform, was induced by retinoic acid (RA) in EC cells, thus suggesting the presence of two promoters in the 5' region of the mRAR-alpha gene, which differ in their response to RA. The conservation between mouse and human RAR-alpha 1 and alpha 2 cDNA isoform sequences, as seen by cross-hybridization in Southern blots or by DNA sequence analysis, together with their differential patterns of expression, strongly suggests that they perform specific functions during embryogenesis and in the adult.

Amino Acid Sequence↗
PubMed1991

Differentially expressed isoforms of the mouse retinoic acid receptor beta generated by usage of two promoters and alternative splicing.

Using anchored PCR, three different cDNA isoforms of the mouse retinoic acid receptor beta [mRAR-beta 1, mRAR-beta 2 (formerly mRAR-beta 0) and mRAR-beta 3], generated from the same gene by differential promoter usage and alternative splicing, were isolated. These three isoforms encode RAR proteins with different N-terminal A regions and identical B - F regions. The sequence encoding the first 59 amino acids of the mRAR-beta 3 A region is identical with the entire A region of mRAR-beta 1. However, the sequence of mRAR-beta 3 region A differs from that of mRAR-beta 1 by an additional 27 C-terminal amino acids encoded in an 81 nucleotide-long putative exon which is spliced in between the exons encoding the A and B regions of mRAR-beta 1. Both mRAR-beta 1 and beta 3 cDNAs differ entirely from mRAR-beta 2 in their 5'-untranslated (5'-UTR) and A region coding sequences. This N-terminal variability, in a region which was shown to be important for cell-type specific differential target gene trans-activation by other nuclear receptors, suggests that the three mRAR-beta isoforms may be functionally distinct. The conservation of RAR-beta isoform sequences from mouse to human, as seen by cross-hybridization on Southern blots or DNA sequence analysis, as well as their differential patterns of expression in various mouse tissues, corroborates this view. Additionally, the mRNA analysis data suggest that mRAR-beta 2, whose expression predominates in RA-treated embryonal carcinoma (EC) and embryonic stem (ES) cells, may be important during early stages of development. mRAR-beta 1 and beta 3, on the other hand, which are predominantly expressed in fetal and adult brain, may play some specific role in the development of the central nervous system.

Amino Acid Sequence↗