Biomedical subjects

M Bernfield

Publications and source records attributed to M Bernfield.

At least 37 records · Page 2Linked to original sources

PubMed1998

Simultaneous loss of expression of syndecan-1 and E-cadherin in the embryonic palate during epithelial-mesenchymal transformation.

Epithelial-mesenchymal transformation (EMT) is the key mechanism for fusion and confluence of the rodent palate. During this process, medial edge epithelia (MEE) form a midline seam that subsequently transforms to mesenchymal cells. We studied syndecan-1 and E-cadherin, two molecules which have been shown to promote the epithelial phenotype, to determine their fate during palatal EMT. We found that both syndecan-1 and E-cadherin are expressed on basolateral surfaces of the MEE at day 14. Twelve hours later, when a midline seam has formed, syndecan-1 and E-cadherin are still present on its basal and lateral epithelial surfaces and they persist after the seam breaks up into epithelial islands. Then, expression of both molecules is lost simultaneously and abruptly when EMT occurs. On the contrary, previous in vitro studies of cell lines transfected with antisense cDNAs suggested that loss of syndecan-1 would lead to loss of E-cadherin or vice versa. We conclude that in vivo, synthesis of both E-cadherin and syndecan-1 is downregulated synchronously by the initiation of EMT, leading to an effective and correctly timed conversion of the epithelial cells to mesenchyme.

Animals↗

PubMed1997

Reduced expression of syndecan-1 in human hepatocellular carcinoma with high metastatic potential.

Syndecans comprise a gene family of transmembrane proteoglycans that regulate cellular behavior through interactions with various effectors, including heparin-binding growth factors and insoluble matrix components. Syndecan-1, the most extensively studied, localizes in epithelial cells and has been shown to present in normal hepatocytes. However, little is known about the change of syndecan-1 expression in human hepatocellular carcinoma (HCC). We investigated syndecan-1-protein expression by immunohistochemistry in 57 HCC tissue samples. Syndecan-1 gene expression was also determined. Syndecan-1 protein was expressed in cytoplasm and cell membrane of the hepatocytes and in the bile duct epithelial cells of liver with underlying hepatitis and cirrhosis. Conversely, among 57 HCC tissues, 39 HCC (68.4%) showed negative staining; 50% of well-differentiated HCC showed positive staining, whereas 82.4% of poorly differentiated HCC were negative. Loss of syndecan-1-protein expression was more prevalent in HCC with intra-hepatic metastasis (85.2%) than those without metastasis (48.0%). Similarly, syndecan-1 expression was significantly reduced in HCC with extra-hepatic metastasis (91.7%) as compared with the HCC without extra-hepatic metastasis (62.2%). The gene expression of syndecan-1 was significantly lower in HCC tissue than that in non-tumoral liver tissue. In 2 human HCC cell lines with poorly differentiated phenotype, HLE and HLF, syndecan-1 expression was markedly decreased both at the mRNA and the protein levels. These results suggest that the loss of syndecan-1 expression is a characteristic feature of HCC with high metastatic potential.

Antibody Specificity↗

PubMed1997

Glycosaminoglycans can influence fibroblast growth factor-2 mitogenicity without significant growth factor binding.

Fibroblast growth factors are important heparin binding, mitogenic proteins. The binding site in heparin and heparan sulfate for fibroblast growth factor-2 (basic fibroblast growth factor) has been described as rich in glucosamine-2-sulfate 1-->4 linked to iduronic acid-2-sulfate. The glucosamine residue in the heparin binding site is also 6-sulfated. A new glycosaminoglycan, acharan sulfate, has been chemically modified to prepare a polysaccharide, N-sulfoacharan sulfate, consisting of glucosamine-2-sulfate 1-->4 linked to iduronic acid-2-sulfate. Acharan sulfate binds very weakly to fibroblast growth factor-2 while N-sulfoacharan sulfate binds with nearly the same affinity as heparin. Mitogenicity studies were performed using heparan sulfate-free cells stably transfected with fibroblast growth factor receptor-1. Acharan sulfate inhibits heparin's enhancement of fibroblast growth factor-2 mitogenic activity, without affecting cell viability, while N-sulfoacharan sulfate shows heparin-like activity but at a greatly reduced level. These results suggest additional mechanisms not requiring high affinity glycosaminoglycan binding to fibroblast growth factor-2 may be important in its mitogenic activity.

Animals↗

PubMed1997

Regulated shedding of syndecan-1 and -4 ectodomains by thrombin and growth factor receptor activation.

The syndecan family of transmembrane heparan sulfate proteoglycans is abundant on the surface of all adherent mammalian cells. Syndecans bind and modify the action of various growth factors/cytokines, proteases/antiproteases, cell adhesion molecules, and extracellular matrix components. Syndecan expression is highly regulated during wound repair, a process orchestrated by many of these effectors. Each syndecan ectodomain is shed constitutively by cultured cells, but the mechanism and significance of this shedding are not understood. Therefore, we examined (i) whether physiological agents active during wound repair influence syndecan shedding, and (ii) whether wound fluids contain shed syndecan ectodomains. Using SVEC4-10 endothelial cells we find that certain proteases and growth factors accelerate shedding of the syndecan-1 and -4 ectodomains. Protease-accelerated shedding is completely inhibited by serum-containing media. Thrombin activity is duplicated by the 14-amino acid thrombin receptor agonist peptide that directly activates the thrombin receptor and is not inhibited by serum. Epidermal growth factor family members accelerate shedding but FGF-2, platelet-derived growth factor-AB, transforming growth factor-beta, tumor necrosis factor-alpha, and vascular endothelial cell growth factor 165 do not. Shed ectodomains are soluble, stable in the conditioned medium, have the same size core proteins regardless whether shed at a basal rate, or accelerated by thrombin or epidermal growth factor-family members and are found in acute human dermal wound fluids. Thus, shedding is accelerated by activation of at least two distinct receptor classes, G protein-coupled (thrombin) and protein tyrosine kinase (epidermal growth factor). Proteases and growth factors active during wound repair can accelerate syndecan shedding from cell surfaces. Regulated shedding of syndecans suggests physiological roles for the soluble proteoglycan ectodomains.

Amino Acid Sequence↗

PubMed1997

Identification of CRAMP, a cathelin-related antimicrobial peptide expressed in the embryonic and adult mouse.

Cathelicidins are the precursors of potent antimicrobial peptides that have been identified in several mammalian species. Prior work has suggested that members of this gene family can participate in host defense through their antimicrobial effects and activate mesenchymal cells during wound repair. To permit further study of these proteins a reverse transcriptase-polymerase chain reaction approach was used to identify potential mouse homologs. A full-length 562-base pair cDNA clone was obtained encoding an NH2-terminal prepro domain homologous to other cathelicidins and a unique COOH-terminal peptide. This gene, named Cramp for cathelin-related antimicrobial peptide, was mapped to chromosome 9 at a region of conserved synteny to which genes for cathelicidins have been mapped in pig and man. Northern blot analysis detected a 1-kilobase transcript that was expressed in adult bone marrow and during embryogenesis as early as E12, the earliest stage of blood development. Reverse transcriptase-polymerase chain reaction also detected CRAMP expression in adult testis, spleen, stomach, and intestine but not in brain, liver, heart, or skeletal muscle. To evaluate further the expression and function of CRAMP, a peptide corresponding to the predicted COOH-terminal region was synthesized. CD spectral analysis showed that CRAMP will form an amphipathic alpha-helix similar to other antimicrobial peptides. Functional studies showed CRAMP to be a potent antibiotic against Gram-negative bacteria by inhibiting growth of a variety of bacterial strains (minimum inhibitory concentrations 0.5-8.0 microM) and by permeabilizing the inner membrane of Escherichia coli directly at 1 microM. Antiserum against CRAMP revealed abundant expression in myeloid precursors and neutrophils. Thus, CRAMP represents the first antibiotic peptide found in cells of myeloid lineage in the mouse. These data suggest that inflammatory cells in the mouse can use a nonoxidative mechanism for microbial killing and permit use of the mouse to study the role such peptides play in host defense and wound repair.

Amino Acid Sequence↗

PubMed1997

Endothelial cell surface alkaline phosphatase activity is induced by IL-6 released during wound repair.

Phosphatase activity on endothelial cell surfaces is responsible, in part, for the conversion of adenosine nucleotides to adenosine, a potent vasodilator and anti-inflammatory mediator that can protect tissues from the ischemic damage that results from injury. To evaluate whether phosphatases are actively induced by a soluble factor released following injury, the effect of tissue fluids collected from porcine or human skin wounds was tested on primary cultures of endothelial cells. Phosphatase activity increased approximately 50-fold following 48-h culture in the presence of wound fluid. Inductive activity was present only in fluids collected during the inflammatory phase of wound repair. The phosphatase activity metabolized adenosine monophosphate to free phosphate and was the liver/bone/kidney alkaline phosphatase isoenzyme: activity was temperature- and levamisole-sensitive, 1-phenylalanine-resistant, and linked to the cell surface via phospholipid, and migrated at a size identical to this isozyme. interleukin-6 was identified as the phosphatase-inducing factor in wound fluid and the related cytokines, leukaemia inhibiting factor, and oncostatin M, caused a similar degree of alkaline phosphatase induction. Therefore, following injury, accumulation of interleukin-6 can lead to production by alkaline phosphatase of adenosine and subsequent protection from ischemic injury.

Adenosine Monophosphate↗

PubMed1996

Transcriptional activation of the syndecan-1 promoter by the Wilms' tumor protein WT1.

The Wilms' tumor suppressor gene (wt1) encodes a zinc finger DNA binding protein (WT1) which functions as a transcriptional regulator and is essential for normal urogenital development. WTI has previously been shown to repress the transcription of a variety of target genes whose products stimulate growth, such as growth factors, growth factor receptors and other transcription factors. In this study, we identify syndecan-1 as a target gene for WT1-mediated activation. Syndecan-1 is a cell surface proteoglycan whose induction is coincident with epithelial differentiation during kidney development and whose loss of expression is correlated with the loss of the epithelial phenotype and malignant transformation. The murine syndecan-1 promoter contains several potential binding sites for WT1. We demonstrate that both WT1 (-KTS) and WT1 (+KTS) isoforms bind to multiple sites in this highly G + C-rich region, as detected by gel-shift analyses. These WT1 isoforms function as transcriptional activators of syndecan-1 expression in transient transfection assays. Activation of syndecan-1 by WT1 is dependent on an intact zinc-finger region as well as a 179 amino acid proline-rich region in the amino terminus of the protein. Moreover, the endogenous syndecan-1 gene is activated by WT1 in a novel inducible cell line based upon the sheep metallothionein promoter. These results highlight an emerging role for WT1 as an activator of genes like syndecan-1 which may potentiate epithelial differentiation and maintenance in the developing kidney.

3T3 Cells↗

PubMed1996

Syndecans-1 and -4 are induced during wound repair of neonatal but not fetal skin.

Syndecans are a family of four cell surface proteoglycans that bind to various components of the extracellular environment and can regulate many cellular behaviors including growth, adhesion, and movement. To determine whether syndecans can function during wound repair, we have examined expression of the syndecans during wound repair of adult mouse and neonatal or fetal human skin. Syndecan-1 and -4 were induced in the dermis within 12 h after incisional injury of murine or neonatal human skin. Syndecan-1 was induced primarily on endothelium, and syndecan-4 was present throughout the dermis at the site of injury. Following re-epithelialization, expression of the syndecans return to their baseline level. In marked contrast to these observations, wounded human fetal skin showed no increase in expression of syndecans. This lack of increase in the expression of syndecans by cells of the dermis correlates with prior observations that fetal skin heals without a polymorphonuclear cell infiltrate, appreciable fibrosis, or clinically apparent scar. Thus, induced expression of syndecans is not an absolute requirement for wound repair but does correlate with the occurrence of fibrosis in mature skin. These findings support the role of syndecans as regulators of cell behavior and suggest that syndecan-1 and -4 induction in the dermis may contribute to events that lead to inflammation and fibrosis.

Animals↗

PubMed1995

A curly-tail modifier locus, mct1, on mouse chromosome 17.

The major gene for neural tube defects, ct, in the curly-tail (CT) mouse strain was mapped previously to mouse chromosome 4 by combining linkage data from several backcrosses. The penetrance of the neural tube trait, already incomplete in the CT strain, was further reduced in several of these backcrosses, suggesting the existence of recessive modifiers or strain-specific susceptibility alleles. Here we describe the mapping of a curly-tail modifier locus, mct1, to chromosome 17 in moderate and low penetrance crosses of CT with BALB/cByJ and Mus spretus. No effect of mct1 was seen in a higher penetrance cross with the BXD-8/Ty strain, confirming that ct is the major gene in the model. Homozygosity at both ct and mct1 loci was sufficient to account for all of the affected individuals in the BALB/cByJ cross and most of the affected individuals in the M. spretus cross and was the preferred model overall. No evidence was found for epistatic interaction between ct and mct1.

Animals↗

PubMed1995

Expression of a Xenopus counterpart of mammalian syndecan 2 during embryogenesis.

We have identified a Xenopus cDNA, XS-2, by screening a Xenopus embryonic stage-22-24 cDNA library with a DNA probe encoding the transmembrane and cytoplasmic domains of mouse syndecan 1. The 1.4 kb cDNA consists of an open reading frame of 642 nucleotides encoding a protein of 191 amino acids. The predicted protein of 20869 Da contains a 25-amino acid putative transmembrane domain and a 32-amino acid putative cytoplasmic domain, both of which are highly similar to the corresponding regions of rat syndecan 2 (92% identity) and to a lesser degree those of rat syndecans 1, 3 and 4 (62, 64 and 78% respectively). The putative N-terminal ectodomain contains a possible attachment site for heparan sulphate, identical with the comparable glycosaminoglycan-attachment sequence of rat syndecan 2. Polyclonal antisera raised against recombinant ectodomain of XS-2, expressed as a fusion protein, recognized a heparan sulphate proteoglycan in XTC cell-culture medium. This proteoglycan bound to DEAE-Sephacel and was eluted with 1 M NaCl; digestion with heparitinase but not chondroitinase ABC resulted in the identification of a 46 kDa protein by these antisera. Northern-blot analysis indicated that XS-2 identifies two Xenopus mRNA species approx. 4 and 2 kb in size in embryos ranging in maturation from the 64-cell stage to stage 54. These results demonstrate that a heparan sulphate proteoglycan, similar to syndecan 2, is expressed during Xenopus embryogenesis.

Amino Acid Sequence↗

PubMed1995

Expression of syndecan-1 changes during the differentiation of visceral and parietal endoderm from murine F9 teratocarcinoma cells.

F9 teratocarcinoma stem cells treated with retinoic acid differentiate in suspension into embryoid bodies with an outer layer of visceral endoderm surrounding a core of largely undifferentiated cells. The visceral endoderm-containing embryoid bodies, when plated onto an extracellular matrix coating, give rise to parietal endoderm outgrowth. These in vitro cell cultures mimic both geometrically and biochemically the differentiation of visceral and parietal endoderm in the early mouse embryo and, thus, were used as a model system for the study of molecular and cellular mechanisms underlying the differentiation of the extraembryonic endoderm lineages. We have investigated the expression of syndecan-1, an integral membrane proteoglycan that binds to multiple components of the extracellular matrix and basic FGF, during visceral endoderm differentiation and parietal endoderm outgrowth. Syndecan-1 immunostaining is detected on all cell surfaces in the undifferentiated embryoid bodies and in the differentiating embryoid bodies prior to the formation of the visceral endoderm. Following the differentiation of visceral endoderm, syndecan-1 localizes predominantly to the basal surface of this epithelial layer, while syndecan-1 staining in the core of differentiated embryoid bodies is faint. Quantitation of cell associated syndecan-1 indicates that syndecan-1 is down-regulated during embryoid body differentiation. However, northern analysis shows that the amounts of steady-state syndecan-1 mRNA are the same in undifferentiated versus differentiated embryoid bodies, suggesting post-transcriptional regulation of syndecan-1 expression in the differentiating embryoid body. Analysis of syndecan-1 distribution in the outgrowth culture by immunofluorescence demonstrates that syndecan-1 is absent from the cell surface of parietal endoderm. However, a substantial amount of syndecan-1 is detected inside parietal endoderm cells. While all three cell types release syndecan-1 ectodomain into the culture medium, the parietal endoderm outgrowth releases more syndecan-1 ectodomain than the differentiated embryoid body. These data suggest that the post-transcriptional control and post-translational shedding of syndecan-1 from the cell surface are developmentally regulated during the differentiation of visceral to parietal endoderm and the migration of parietal endoderm.

Animals↗

PubMed1995

Loss of cell surface syndecan-1 causes epithelia to transform into anchorage-independent mesenchyme-like cells.

Simple epithelial cells are polygonal in shape, polarized in an apical-basal orientation, and organized into closely adherent sheets, characteristics that result from a variety of cellular specializations and adhesive proteins. These characteristics are lost when the epithelia transform during embryogenesis into mesenchymal cells or after neoplasia into invasive carcinoma cells. Of the syndecan family of transmembrane heparan sulfate proteoglycans, simple epithelia produce predominantly syndecan-1, which is found at basolateral surfaces and within adhesive junctions. To elucidate the function of this syndecan-1, normal murine mammary gland epithelia were made deficient in syndecan-1 by transfection with an expression vector containing the syndecan-1 cDNA in the antisense configuration. Several independently derived clones of stable transfectants contained the antisense cDNA in their genome and expressed the antisense transcript. These grew either as epithelial islands of closely adherent polygonal cells, identical to both the parental cells and the vector-only control transfectants, or as individual elongated fusiform cells that invaded and migrated within collagen gels, like mesenchymal cells, but were anchorage-independent for growth. The clones that retained epithelial characteristics were moderately deficient in cell surface syndecan-1 (greater than 48% of control levels) but did not differ from control cells in expression of beta 1-integrins and E-cadherin, or in F-actin organization. However, the clones of fusiform cells were severely deficient in cell surface syndecan-1 (less than 12% of control levels) and showed rearranged beta 1-integrins, markedly reduced E-cadherin expression, and disorganized F-actin filaments, but retained mammary epithelial markers. Therefore, depleting epithelia of cell surface syndecan-1 alters cell morphology and organization, the arrangement and expression of adhesion molecules, and anchorage-dependent growth controls. Thus, cell surface syndecan-1 is required to maintain the normal phenotype of simple epithelia.

Actins↗

PubMed1994

Syndecans, cell surface heparan sulfate proteoglycans, are induced by a proline-rich antimicrobial peptide from wounds.

Cell surface heparan sulfate proteoglycans, such as the syndecans, are required for cellular responses to heparin-binding growth factors and extracellular matrix components. Expression of syndecan-1 and -4 is induced in mesenchymal cells during wound repair in the mouse, consistent with a role for syndecans in regulating cell proliferation and migration in response to these effectors. Here we show that wound fluid contains inductive activity that mimics the in vivo induction in time of appearance, specificity for mesenchymal cells, and selectivity for syndecan-1 and -4. We have purified and synthesized a 4.8-kDa proline-rich protein from wound fluid that reproduces this induction of syndecan-1 and -4 in cultured cells. This peptide, identical to the antibacterial peptide PR-39, is released into the wound by the cellular infiltrate and induces syndecan expression at the same peptide concentrations that lyse bacteria. These results indicate that wounds contain a multifunctional protein that induces mammalian cells to express cell surface heparan sulfate proteoglycans as part of the wound repair process and that kills bacteria as part of a nonimmune defense mechanism.

3T3 Cells↗

PubMed1994

Cell surface syndecan-1 on distinct cell types differs in fine structure and ligand binding of its heparan sulfate chains.

Heparan sulfate (HS) can bind a large variety of biological effectors, including extracellular matrix components, growth factors, chemokines, degradative enzymes, and protease inhibitors. Where studied, HS is known to be structurally heterogeneous and to vary in sulfation pattern between cells and tissues. Because heparan sulfate can represent several distinct proteoglycans, we asked whether the structural variation in the heparan sulfate chains of a single species of cell surface proteoglycan is a reproducible, differentiated characteristic and whether the variation can result in distinct biological functions. We studied the molecular structure and binding affinity for type I collagen and fibroblast growth factor-2 of syndecan-1 purified from the surfaces of NMuMG normal murine mammary gland epithelia, NIH/3T3 fibroblasts, and BALB/3T3 endothelioid cells. Syndecan-1 from these cell types varied in molecular mass largely due to variation in the length of the HS chains. Although the highly sulfated and N-acetylated domains in these HS chains were organized similarly, the number of highly sulfated domains differed. The disaccharide compositions were also similar except for reproducible and consistent differences in the amount of hexuronic acid-N-sulfated-6-O-sulfated glucosamine and 2-O-sulfated hexuronic acid-N-sulfated glucosamine. These differences were confirmed by oligosaccharide mapping, which showed cell type-specific variations in the composition of the highly sulfated domains. These structural variations correlated with cell type-specific differences in the affinity of syndecan-1 and its isolated HS chains for type I collagen. However, no differences in affinity for fibroblast growth factor-2 were detected. The results indicate that the size, fine structure, and ligand affinity of the HS chains on a single proteoglycan species differ in a consistent and reproducible manner between cell types. Thus, the variation in structure and binding ability of HS on syndecan-1 is a differentiated characteristic of the cell type that can enable cells to respond distinctly to the HS-binding effectors in the cellular microenvironment.

3T3 Cells↗

PubMed1994

Core protein structure and sequence determine the site and presence of heparan sulfate and chondroitin sulfate on syndecan-1.

Most proteoglycans bear either chondroitin sulfate or heparan sulfate chains linked to serine residues at Ser-Gly attachment sites on the core protein. However, only a fraction of proteins with Ser-Gly sites exhibit glycosaminoglycan chains. A variable proportion of these sites may be glycanated, and an unknown mechanism distinguishes whether these sites are for chondroitin sulfate or heparan sulfate. To evaluate the core protein features that determine whether and where chondroitin sulfate or heparan sulfate will be linked, we have studied mouse syndecan-1, a transmembrane proteoglycan that is invariably glycanated and can contain both chondroitin sulfate and heparan sulfate chains. The extracellular domain of the syndecan-1 core protein contains five Ser-Gly sites, three clustered near its N terminus and two adjacent to the transmembrane domain near its C terminus. We have established the distribution of glycosaminoglycans on these attachment clusters. In contrast to the C-terminal cluster, the N-terminal cluster was always glycanated, suggesting that this domain of the core protein contains sequences responsible for the invariable attachment of glycosaminoglycan chains. Solely chondroitin sulfate was found on the C-terminal cluster. This cluster contains the sequences EGSGE and ETSGE, both estimated to be on the protein surface in a hydrophilic environment. Heparan sulfate was found solely on the N-terminal cluster, which also bears some chondroitin sulfate. This cluster contains the sequences FSGSGTG and DGSGD, the former estimated to be in a hydrophobic pocket and the latter, similar to the sequence on the C-terminal cluster, in an exposed hydrophilic region. This glycosaminoglycan distribution was identical on mouse syndecan-1 produced by either mouse epithelial (NMuMG) or hamster mesenchymal (CHO) cells, suggesting that site-specific attachment of glycosaminoglycans is independent of cell type. These results implicate a cellular mechanism that distinguishes among the potential sites and attaches the correct glycosaminoglycan type unambiguously. Thus, structural elements of the core protein other than the Ser-Gly attachment sites determine if a site will be glycanated and, if so, whether with chondroitin sulfate or heparan sulfate.

Amino Acid Sequence↗

PubMed1994

Drosophila syndecan: conservation of a cell-surface heparan sulfate proteoglycan.

In mammals, cell-surface heparan sulfate is required for the action of basic fibroblast growth factor, fibronectin, antithrombin III, as well as other effectors. The syndecans, a gene family of four transmembrane proteoglycans that participates in these interactions, are the major source of this heparan sulfate. Based on the conserved transmembrane and cytoplasmic domains of the mammalian syndecans, a single syndecan-like gene was detected and localized in the Drosophila genome. As in mammals, Drosophila syndecan is a heparan sulfate proteoglycan expressed at the cell surface that can be shed from cultured cells. The single Drosophila syndecan is expressed in embryonic tissues that correspond with those tissues in mammals that express distinct members of the syndecan family predominantly. Conservation of this class of molecules suggests that Drosophila, like mammals, uses cell-surface heparan sulfate as a receptor or coreceptor for extracellular effector molecules.

Amino Acid Sequence↗

PubMed1994

Mapping of the syndecan genes in the mouse: linkage with members of the myc gene family.

The syndecans are a family of four cell surface heparan sulfate proteoglycans in vertebrates that mediate a variety of cell behaviors, including cell adhesion and the action of growth factors. Their core proteins contain conserved transmembrane and cytoplasmic domains but divergent extracellular regions in which only the glycosaminoglycan attachment sites are conserved. By extensive PCR analyses based on the conserved sequences, we find only four syndecan-related sequences in the mouse. These correspond to the previously described core proteins of syndecan proteoglycans from other vertebrates. We have mapped the genes for syndecan-2 to chromosome 15, syndecan-3 to chromosome 4, and syndecan-4 to chromosome 2 in the mouse. Together with the previous localization of the gene for syndecan-1 to chromosome 12, these data establish that the four syndecan genes are dispersed on different chromosomes and that each syndecan gene is located near a member of the myc gene family. Synd1 is next to Nmyc, Synd2 close to myc, Synd3 near Lmyc, and Synd4 on the same chromosome as Bmyc. The physical relationship between the members of these two gene families appears to be ancient and conserved after the two genome duplications thought to have occurred during vertebrate evolution.

Animals↗

PubMed1994

Multifactorial inheritance of neural tube defects: localization of the major gene and recognition of modifiers in ct mutant mice.

Neural tube defects (NTD) in humans have been considered to have a multifactorial aetiology, however the participating genes have not been identified. The curly-tail (ct) mutant mouse develops NTD that resemble the human malformations in location, pathology and associated abnormalities. Moreover, there appears to be multifactorial influence on the incidence of NTD in offspring of curly-tail mice. We now describe a linkage analysis that localizes the ct gene to distal chromosome 4 in mice. Further analysis using recombinant inbred strains demonstrates the presence of at least three modifier loci that influence the incidence of NTD. This study provides definitive evidence for multifactorial inheritance in a mouse model of human NTD.

Abnormalities, Multiple↗