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PubMed2001

Screening of differentially expressed genes in 5-fluorouracil-resistant human gastrointestinal tumor cells.

To identify genes differentially expressed in association with resistance to 5-fluorouracil (5FU), an mRNA differential display (DD) analysis was used to compare transcripts from the NUGC-3 human gastric tumor cell line and the NUGC-3 / 5FU / L line, which had acquired 208-fold resistance as a consequence of repeated exposure to escalating concentrations of 5FU. The 110 cDNA fragments differentially expressed in the DD analysis of either the NUGC-3 or NUGC-3 / 5FU / L cells were sequenced and subjected to a homology search, and 29 overexpressed and 22 underexpressed genes were identified in NUGC-3 / 5FU / L as a result. To confirm whether the changes in the gene expression levels in the NUGC-3 / 5FU / L cells were shared by other 5FU-resistant cells, 35 genes were analyzed by northern hybridization in 3 pairs of parent / 5FU-resistant human gastrointestinal tumor cell lines. The analysis revealed 20 overexpressed and 10 underexpressed genes in at least one of the three 5FU-resistant cells as compared with those in the parent cells. Among them, P-glycoprotein, equilibrative nucleoside transporter 1, and methylenetetrahydrofolate dehydrogenase were highly expressed in two of the three 5FU-resistant cells and cytidine deaminase and integrin alpha3 were underexpressed. The acquisition of resistance to 5FU by tumor cells may result from multiple changes in cellular functions.

Antimetabolites, Antineoplastic↗
PubMed1998

Modulation of laminin integrin receptors in the postnatal and adult rat lung.

Recent studies have shown that type II pneumocytes, at birth and day 3 postnatally, have a diffuse distribution and localize at alveolar 'corners' between 3 and 7 days. Since alpha 3 beta 1 and alpha 6 beta 1 are laminin-binding receptors that are well expressed by rat type II alveolar epithelial cells, we postulated that they may play a role in the localization of the cells in the alveolus. To begin the evaluation of this hypothesis, we studied the temporal and spatial expression of the alpha 3, alpha 6, and beta 1 integrin subunit protein and mRNA in whole rat lungs during postnatal development by immunofluorescence, confocal microscopy, and Northern blot analysis. The temporal expression of proteins analyzed by immunochemistry, with integrin subunit specific antibodies, increased during the 3- to 7-day postnatal period and in adult lungs. Densitometric values of the alpha 3, alpha 6, and beta 1 mRNA expression, normalized to 28S rRNA, quadrupled from day 1 to day 3 postnatally. The mRNA expression of different integrin chains was elevated 1.5- to threefold from days 5 to 7 postnatally compared to day 1 levels. The alpha 3 and alpha 6 integrin subunit mRNA decreased to newborn levels in adult lungs, whereas the beta 1 integrin mRNA in adult lungs was expressed at approximately 50% of its level in newborn lungs. We postulate that the increases in alpha 3, alpha 6, and beta 1 integrin mRNA expression during the early neonatal period may be important for the spatial distribution of type II pneumocytes.

Aging↗
PubMed1998

Phenotypic characterization of rat hepatoma cell lines and lineage-specific regulation of gene expression by differentiation agents.

Hepatoma cell lines can be characterized by their expression of hepatocyte- and biliary-specific genes and by their response to differentiating agents in a lineage-dependent manner. These characteristics can be used to map the maturational lineage position of the cell lines. Tissue-specific gene expression and regulation by heparin, dimethylsulfoxide (DMSO), and sodium butyrate (SB) were examined in three rat hepatoma cell lines and two rat liver epithelial cell lines. Based on antigenic profiles and gene expression in serum-supplemented medium, the hepatoma cell lines could be organized in distinct categories of hepatic differentiation. All three hepatomas expressed the following five genes: gamma-glutamyl transpeptidase (GGT), glutathione-S-transferase pi (Yp), glutamine synthetase, and alpha 5 and beta 1 integrin. Cell line H4AzC2 also expressed alpha-fetoprotein (AFP), albumin. IGF II receptor, and the biliary/oval cell antigens OC.2 and OC.3, a phenotype characteristic of fetal hepatocytes. FTO-2B cells lacked AFP, OC.2, and OC.3 but expressed albumin and IGF II receptor in addition to the five commonly expressed genes, consistent with a more hepatocyte-like phenotype. Cell line H5D-7 expressed neither albumin nor the IGF II receptor, but did express OC.2, OC.3, and alpha 3 integrin in addition to the five commonly expressed genes, characteristic of biliary epithelial cells. Regulation of gene expression by heparin, DMSO, and SB was examined in cells cultured in hormonally defined medium. The patterns of regulation of AFP, albumin, GGT, and Yp were dependent upon the state of differentiation of the cell. FTO-2B cells regulated genes in a manner similar to that of E16 fetal hepatocytes, H4AzC2 regulated genes characteristic of both hepatocytic and biliary lineages, and H5D.7 regulated only biliary genes. Suppression of GGT by DMSO was uniformly observed. The three cell lines expressed equal amounts of HNF-4, but FTO-2B cells expressed more HNF-3 beta and less HNF-3 alpha, while the reverse was true of H4AzC2 and H5D.7 cells.

Animals↗
PubMed2006

The Muscleblind family of proteins: an emerging class of regulators of developmentally programmed alternative splicing.

Alternative splicing is widely used to generate protein diversity and to control gene expression in many biological processes, including cell fate determination and apoptosis. In this review, we focus on the Muscleblind family of tissue-specific alternative splicing regulators. Muscleblind proteins bind pre-mRNA through an evolutionarily conserved tandem CCCH zinc finger domain. Human Muscleblind homologs MBNL1, MBNL2 and MBNL3 promote inclusion or exclusion of specific exons on different pre-mRNAs by antagonizing the activity of CUG-BP and ETR-3-like factors (CELF proteins) bound to distinct intronic sites. The relative activities of Muscleblind and CELF proteins control a key developmental switch. Defined transcripts follow an embryonic splice pattern when CELF activity predominates, whereas they follow an adult pattern when Muscleblind activity prevails. Human MBNL proteins show functional specializations. While MBNL1 seems to promote muscle differentiation, MBNL3 appears to function in an opposing manner inhibiting expression of muscle differentiation markers. MBNL2, on the other hand, participates in a new RNA-dependent protein localization mechanism involving recruitment of integrin alpha3 protein to focal adhesions. Both muscleblind mutant Drosophila embryos and Mbnl1 knockout mice show muscle abnormalities and altered splicing of specific transcripts. In addition to regulating terminal muscle differentiation through alternative splicing control, results by several groups suggest that Muscleblind participates in the differentiation of photoreceptors, neurons, adipocytes and blood cell types. Misregulation of MBNL activity can lead to human pathologies. Through mechanisms not completely identified yet, expression of transcripts containing large non-coding CUG or CCUG repeat expansions mimics muscleblind loss-of-function phenotypes. Archetypical within this class of disorders are myotonic dystrophies. Our understanding of the biology of Muscleblind proteins has increased dramatically over the last few years, but several key issues remain unsolved. Defining the mechanism of the activity of Muscleblind proteins, their splicing partners, and the functional relevance of its several protein isoforms are just a few examples.

Alternative Splicing↗
PubMedDate not supplied

Localization of adhesion molecules on human spermatozoa by fluorescence microscopy.

The expression of adhesion molecules on human spermatozoa of healthy probands was analysed. The localization patterns of adhesion molecules (AM) on the spermatozoal surface were documented by fluorescence microscopy. Spermatozoa were incubated with antibodies against alpha 1 (CD49a), alpha 2 (CD49b), alpha 3 (CD49c), alpha 4 (CD49d), alpha 5 (CD49e), alpha 6 (CD49f) chains of beta 1 integrins, beta 1 (CD29), beta 2 (CD18), alpha V (CD51), beta 3 (CD61) and beta 4 integrin chains, the LFA-3 (Lymphocyte function antigen, CD58) from the immunoglobulin superfamily and the extra-cellular matrix proteins laminin, fibronectin and collagen IV. For collagen IV, alpha 1 and alpha 2 chains no expression could be noticed. Laminin was detected at the acrosomal membrane, fibronectin and beta 4 chain mainly at the equatorial membrane. The fibronectin receptors alpha 3, alpha 4 and alpha 5 chains of the beta 1 integrins were mainly located on acrosomal and equatorial membrane areas. Laminin receptor alpha 6 chain was located postacrosomal and less frequently acrosomal. beta 2 chain and vitronectin receptors alpha V and beta 3 chains had a mainly postacrosomal localization pattern. LFA-3 was found constantly on postacrosomal membrane areas. Double staining technique was used to prove the simultaneous occurrence of fibronectin and its integrin receptors alpha 3, alpha 4 and alpha 5 chains and of alpha V and beta 2 chains on spermatozoa. The localization patterns of integrins on double stained spermatozoa were similar to the patterns described for single stained spermatozoa. The localization of fibronectin appeared to be influenced by the presence of integrins: the typical equatorial fibronectin band disappeared in case of an equatorial localization of integrins.

Antigens, CD↗
PubMed1997

Expression of integrin subunits and CD44 isoforms in psoriatic skin and effects of topical calcitriol application.

Increasing evidence suggests involvement of integrins and CD44 isoforms in the pathogenesis of psoriasis, contributing to uncontrolled keratinocyte proliferation, neovascularization, and invasion of inflammatory cells. We have analyzed immunohistochemically in situ expression of integrins (CD29, CDw49b, CDw49c, CDw49e, CDw49f) and CD44 isoforms (CD44 standard, CD44 var/v6, CD44 v10) on frozen sections of normal and psoriatic skin (nonlesional skin, lesional skin before and along with topical calcitriol treatment). We did not observe visual changes of immunoreactivity in normal as compared to nonlesional psoriatic skin, while the staining pattern of CDw49c, CDw49f, and CD29 was severely altered in untreated lesional psoriatic skin. Most markedly, CDw49c, CDw49f, and CD29 were focally upregulated in suprapapillar epidermal compartments of lesional psoriatic skin, a staining pattern that is in accordance with the phenomenon that was described by Pinkus as "squirting papilla". Additionally, an increased proportion of inflammatory and endothelial cells revealed immunoreactivity for CD44(std.) in untreated lesional psoriatic as compared to nonlesional psoriatic or normal skin. After 8 weeks of topical calcitriol treatment (15 micrograms/g ointment), the staining pattern for CDw49c, CDw49f and CD29 was markedly changed in epidermis of lesional psoriatic skin, reverting to the staining pattern characteristic for the nonlesional psoriatic or normal human skin, although epidermal expression of CDw49f was still upregulated and CDw49e-, CDw49f-, CD29-, and CD44(std.)-immunoreactive inflammatory and endothelial cells were still to be found in the dermal compartment.

Administration, Topical↗
PubMed2004

Expression patterns of integrins on pleomorphic adenoma and adenoid cystic carcinoma: study on specimens and in vitro investigation of the effects of extracellular matrix on the expression of these adhesion molecules.

BACKGROUND: Pleomorphic adenoma (PA) and adenoid cystic carcinoma (ACC) are neoplasms of distinct behaviour, showing similar origin, cell components and marked presence of extracellular matrix (ECM). Interactions between cells and ECM are important in the biology of tumours, being partially mediated by integrins. This study investigated these interactions on PA and ACC using paraffin-embedded tissue and an in vitro model of these conditions. METHODS: Expression of integrins in paraffin-embedded samples was assessed by immunohistochemistry. Cells from PA and ACC were characterized using immunofluorescence, and integrin patterns of expression were investigated on cells cultivated on different ECM proteins. RESULTS: Luminal cells of both PA and ACC were more intensely positive for integrins than myoepithelial cells. In vitro studies revealed that PA cells expressed more integrins than ACC cells regardless the ECM protein present. CONCLUSIONS: This study revealed particular patterns of integrin expression in both specimens and in vitro models of PA and ACC. This might prove useful for a better understanding of the biology of these lesions.

Actins↗
PubMed1998

Immunodetection of cell adhesion molecules in rat Sertoli cell cultures.

PROBLEM: The presence of cell adhesion molecules (CAMs) in Sertoli cells has not been explored extensively. The expression of CAMs involved in cell-matrix and cell-to-cell interactions in Sertoli cell cultures was examined. METHOD OF STUDY: Immunohistochemical and Western blot techniques were applied to rat Sertoli cell cultures using specific antibodies to alpha 3, alpha 5, and alpha 6 integrin subunits; NCAM; and cadherins. RESULTS: Expression of alpha 3 and alpha 6 integrin subunits (mainly laminin receptors) and lack of expression of alpha 5 integrin subunit (fibronectin receptor) was observed in Sertoli cells by immunohistochemistry. These cells also expressed neural CAM (NCAM) and N-cadherin. By Western blot analysis, Sertoli cell extracts reacted with antibodies to alpha 3 integrin subunit revealed a band approximately 130 kDa, whereas no expression of alpha 5 integrin subunit was detected. Cell extracts incubated with antibodies to pan cadherin exhibited a band approximately 120 kDa, whereas bands of 180, 140, and 120 kDa were observed with antibodies to NCAM. CONCLUSION: New data about the expression of receptors for extracellular matrix proteins (alpha 3 and alpha 6 integrin subunits) as well as cell-to-cell adhesion molecules (NCAM and cadherins) are reported in rat Sertoli cell cultures.

Animals↗
PubMed2001

Calprotectin expression inhibits bacterial binding to mucosal epithelial cells.

Squamous mucosal epithelial cells constitutively express calprotectin in the cytoplasm. To study how this antimicrobial protein complex confers epithelial resistance to invading bacteria, an epithelial cell line was stably transfected to express the calprotectin complex. Cells expressing calprotectin resist invasion by Listeria monocytogenes and Salmonella enterica serovar Typhimurium. Calprotectin expression was accompanied by altered actin organization, increased alpha3 integrin expression, and spreading cell morphology. In this study, we assessed whether calprotectin expression affects bacterial binding and uptake. Threefold-fewer Listeria organisms bound to the surfaces of calprotectin-expressing cells, and 10-fold fewer were localized intracellularly by immunofluorescence. Similarly, fewer Salmonella organisms bound to cells expressing calprotectin. Calprotectin-expressing and sham-transfected cells showed similar levels of expression of surface E-cadherin and intracellular adhesion molecule 1 (ICAM-1) by flow cytometry. Calprotectin-expressing transfectants expressed calprotectin on the cell surface as well as in the cytosol. In conclusion, two bacterial pathogens showed reduced binding to calprotectin-expressing epithelial cells. Calprotectin-expressing cells appeared to have internalized disproportionately fewer Listeria organisms, suggesting that reduced binding and translocation supplemented direct antimicrobial effects in calprotectin-expressing cells.

Bacterial Adhesion↗
PubMed1998

Activation of Rho-dependent cell spreading and focal adhesion biogenesis by the v-Crk adaptor protein.

The small GTPase RhoA plays a critical role in signaling pathways activated by serum-derived factors, such as lysophosphatidic acid (LPA), including the formation of stress fibers in fibroblasts and neurite retraction and rounding of soma in neuronal cells. Previously, we have shown that ectopic expression of v-Crk, an SH2/SH3 domain-containing adapter proteins, in PC12 cells potentiates nerve growth factor (NGF)-induced neurite outgrowth and promotes the survival of cells when NGF is withdrawn. In the present study we show that, when cultured in 15% serum or lysophosphatidic acid-containing medium, the majority of v-Crk-expressing PC12 cells (v-CrkPC12 cells) display a flattened phenotype with broad lamellipodia and are refractory to NGF-induced neurite outgrowth unless serum is withdrawn. v-Crk-mediated cell flattening is inhibited by treatment of cells with C3 toxin or by mutation in the Crk SH2 or SH3 domain. Transient cotransfection of 293T cells with expression plasmids for p160ROCK (Rho-associated coiled-coil-containing kinase) and v-Crk, but not SH2 or SH3 mutants of v-Crk, results in hyperactivation of p160ROCK. Moreover, the level of phosphatidylinositol-4,5-bisphosphate is increased in v-CrkPC12 cells compared to the levels in mutant v-Crk-expressing cells or wild-type cells, consistent with PI(4)P5 kinase being a downstream target for Rho. Expression of v-Crk in PC12 cells does not result in activation of Rac- or Cdc42-dependent kinases PAK and S6 kinase, demonstrating specificity for Rho. In contrast to native PC12 cells, in which focal adhesions and actin stress fibers are not observed, immunohistochemical analysis of v-CrkPC12 cells reveals focal adhesion complexes which are formed at the periphery of the cell and are connected to actin cables. The formation of focal adhesions correlates with a concomitant upregulation in the expression of focal adhesion proteins FAK, paxillin, alpha3-integrin, and a higher-molecular-weight form of beta1-integrin. Our results indicate that v-Crk activates the Rho-signaling pathway and serves as a scaffolding protein during the assembly of focal adhesions in PC12 cells.

Animals↗
PubMed2000

Integrin alpha(3)-subunit expression modulates alveolar epithelial cell monolayer formation.

We investigated expression of the alpha(3)-integrin subunit by rat alveolar epithelial cells (AECs) grown in primary culture as well as the effects of monoclonal antibodies with blocking activity against the alpha(3)-integrin subunit on AEC monolayer formation. alpha(3)-Integrin subunit mRNA and protein were detectable in AECs on day 1 and increased with time in culture. alpha(3)- and beta(1)-integrin subunits coprecipitated in immunoprecipitation experiments with alpha(3)- and beta(1)-subunit-specific antibodies, consistent with their association as the alpha(3)beta(1)-integrin receptor at the cell membrane. Treatment with blocking anti-alpha(3) monoclonal antibody from day 0 delayed development of transepithelial resistance, reduced transepithelial resistance through day 5 compared with that in untreated AECs, and resulted in large subconfluent patches in monolayers viewed by scanning electron microscopy on day 3. These data indicate that alpha(3)- and beta(1)-integrin subunits are expressed in AEC monolayers where they form the heterodimeric alpha(3)beta(1)-integrin receptor at the cell membrane. Blockade of the alpha(3)-integrin subunit inhibits formation of confluent AEC monolayers. We conclude that the alpha(3)-integrin subunit modulates formation of AEC monolayers by virtue of the key role of the alpha(3)beta(1)-integrin receptor in AEC adhesion.

Animals↗
PubMed1997

Podocyte alpha-actinin induction precedes foot process effacement in experimental nephrotic syndrome.

Attachment of podocytes to the glomerular basement membrane is thought to be mediated primarily by alpha 3/beta 1-integrins and by cytoskeletal proteins including actin, talin, vinculin, and alpha-actinin. We analyzed the expression of those molecules in rat glomeruli at several time points during induction of podocyte foot process effacement and nephrotic syndrome with puromycin aminonucleoside (PAN). PAN injection resulted in marked induction of glomerular alpha-actinin (40% increase vs. paired controls, P < 0.01), which clearly preceded development of podocyte foot process effacement and proteinuria and localized almost exclusively to podocytes. Delayed induction of glomerular alpha 3-integrin (44% increase vs. paired controls, P < 0.01) following foot process effacement was also observed but was not restricted to podocytes. No significant changes in glomerular vinculin, talin, beta 1-integrin, or total actin expression occurred at any time point during disease development. We conclude that foot process effacement is preceded by induction of alpha-actinin in podocytes in experimental nephrotic syndrome. Altered expression of this actin cross-linking protein in podocytes may have a pathogenic role in foot process effacement in nephrotic syndrome.

Actinin↗
PubMed1997

An Arg-Gly-Asp peptide stimulates constriction in rat afferent arteriole.

The potential role of integrins in the myogenic mechanism was studied in the rat afferent arteriole (AA) by fluorescence immunolocalization and microperfusion of isolated AA. Confocal fluorescence images were acquired from frozen sections of rat kidney after indirect immunostaining for various integrin beta- and alpha-subunits. The beta 1-, beta 3-, alpha 3-, alpha 5-, and alpha V-integrins were found on the plasma membrane in smooth muscle of AA, providing the morphological basis for participation of integrins in mechanotransduction. With 1 mM nitro-L-arginine methyl ester (L-NAME) in the luminal perfusate to inhibit endogenous nitric oxide (NO) production from AA, the hexapeptide GRGDSP (10(-7)-10(-3)M) induced immediate vasoconstriction. The constriction was dose dependent and specific or peptides with arginine-glycine-aspartic acid (RGD) motifs, commonly found on the binding sites of extracellular matrix to integrins. In controls, the hexapeptide GRGESP induced no constriction. GRGDSP, 1 mM, induced a 21.6 +/- 2.6% decrease (P < 0.05, n = 6) in lumen diameter for 30 s and an 18.3 +/- 4.1% increase (P < 0.05, n = 6) in smooth muscle intracellular calcium concentration for 18 s, as measured by the emission ratio of Fluo-3/Fura Red. Binding of exogenous RGD motifs with exposed integrins on AA smooth muscle therefore triggers calcium-dependent vasoconstriction. However, the dose response to RGD was not sensitive to the myogenic tone of the vessel, which suggests that the integrin-mediated vasoconstriction is different from myogenic constriction.

Amino Acid Sequence↗
PubMed2005

Homeobox D10 induces phenotypic reversion of breast tumor cells in a three-dimensional culture model.

Homeobox (Hox) genes are master regulatory genes that direct organogenesis and maintain differentiated tissue function. We previously reported that HoxD10 helps to maintain a quiescent, differentiated phenotype in endothelial cells by suppressing expression of genes involved in remodeling the extracellular matrix and cell migration. Here we investigated whether HoxD10 could also promote or maintain a differentiated phenotype in epithelial cells. We observed that HoxD10 expression is progressively reduced in epithelial cells as malignancy increases in both breast and endometrial tumors. Retroviral gene transfer to restore expression of HoxD10 in the malignant breast tumor cells MDA-MB-231 significantly impaired migration, and when these cells were cultured in a three-dimensional laminin-rich basement membrane (3DlrBM) model, they formed polarized, acinar structures. This phenotypic reversion was accompanied by decreased alpha3 integrin expression and reduced proliferation. Importantly, expression of HoxD10 in the MDA-MB-231 cells inhibited their ability to form tumors in mouse xenografts. Taken together, our results suggest that HoxD10 has tumor-suppressive functions for mammary epithelial cells.

Animals↗
PubMed2006

Messenger RNAs under differential translational control in Ki-ras-transformed cells.

Microarrays have been used extensively to identify differential gene expression at the level of transcriptional control in oncogenesis. However, increasing evidence indicates that changes in translational control are critical to oncogenic transformation. This study identifies mRNA transcripts that are differentially regulated, primarily at the level of translation, in the immortalized human embryonic prostate epithelial cell line 267B1 and the v-Ki-ras-transformed counterpart by comparing total mRNA to polysome-bound mRNA by using Affymetrix oligonucleotide microarrays. Among the transcripts that were identified were those encoding proteins involved in DNA replication, cell cycle control, cell-to-cell interactions, electron transport, G protein signaling, and translation. Many of these proteins are known to contribute to oncogenesis or have the potential to contribute to oncogenesis. Differential expression of RNA-binding proteins and the presence of highly conserved motifs in the 5' and 3' untranslated regions of the mRNAs are consistent with multiple pathways and mechanisms governing the changes in translational control. Although Alu sequences were found to be associated with increased translation in transformed cells, an evolutionarily conserved motif was identified in the 3' untranslated regions of ephrinB1, calreticulin, integrin alpha3, and mucin3B that was associated with decreased polysome association in 267B1/Ki-ras.

3' Untranslated Regions↗
PubMed2006

Mesenchymal progenitor cells communicate via alpha and beta integrins with a three-dimensional collagen type I matrix.

BACKGROUND/AIMS: The aim of our study was to investigate interactions of mesenchymal progenitor cells (MPCs) with collagen matrices. METHODS: Human bone-marrow-derived MPCs were cultivated in collagen type I gels with and without inhibition of beta(1)-integrin by a specific antibody. Collagen gel contraction, cell morphology, expression of integrin subunits and several genes related to matrix synthesis and turnover as well as MPC differentiation were analyzed over 14 days. RESULTS: Human MPCs markedly contracted free-floating collagen gels. Contraction was nearly completely inhibited by blocking beta(1)-integrin. Cellular morphology was elongated in the absence and mostly round in the presence of the antibody. Expression of integrin alpha(1), alpha(2) and beta(1) subunits showed several changes partly dependent on beta(1)-integrin blocking. Expression of matrix metalloproteinase-1 was elevated irrespective of beta(1)-integrin blocking and tenascin-C was subsequently induced during gel contraction. Spontaneous induction of chondrogenic, osteogenic or adipogenic differentiation was observed neither in the presence nor in the absence of the beta(1)-integrin antibody. CONCLUSION: Our results indicate that the interaction of human MPCs with fibrillar collagen type I involves beta(1)- and alpha-integrin subunits and induces changes in gene expression related to extracellular matrix synthesis and turnover but not differentiation to the chondrogenic, osteogenic or adipogenic phenotype.

Antibodies, Monoclonal↗
PubMed2002

Transcriptional induction of slit diaphragm genes by Lmx1b is required in podocyte differentiation.

LMX1B encodes a LIM-homeodomain transcription factor. Mutations in LMX1B cause nail-patella syndrome (NPS), an autosomal dominant disease with skeletal abnormalities, nail hypoplasia, and nephropathy. Expression of glomerular basement membrane (GBM) collagens is reduced in Lmx1b(-/-) mice, suggesting one basis for NPS nephropathy. Here, we show that Lmx1b(-/-) podocytes have reduced numbers of foot processes, are dysplastic, and lack typical slit diaphragms, indicating an arrest in development. Using antibodies to podocyte proteins important for podocyte function, we found that Lmx1b(-/-) podocytes express near-normal levels of nephrin, synaptopodin, ZO-1, alpha3 integrin, and GBM laminins. However, mRNA and protein levels for CD2AP and podocin were greatly reduced, suggesting a cooperative role for these molecules in foot process and slit diaphragm formation. We identified several LMX1B binding sites in the putative regulatory regions of both CD2AP and NPHS2 (podocin) and demonstrated that LMX1B binds to these sequences in vitro and can activate transcription through them in cotransfection assays. Thus, LMX1B regulates the expression of multiple podocyte genes critical for podocyte differentiation and function. Our results indicate that reduced levels of proteins associated with foot processes and the glomerular slit diaphragm likely contribute, along with reduced levels of GBM collagens, to the nephropathy associated with NPS.

Animals↗