Biomedical subjects

X Zhou

Publications and source records attributed to X Zhou.

At least 235 records · Page 13Linked to original sources

PubMed2000

Multiple infection, recombination and genome relationships among begomovirus isolates found in cotton and other plants in Pakistan.

Begomoviruses occur in many plant species in Pakistan and are associated with an epidemic of cotton leaf curl disease that has developed since 1985. PCR analysis with primer pairs specific for each of four already sequenced types of DNA-A of cotton leaf curl virus (CLCuV-PK types a, 26, 72b and 804a), or for okra yellow vein mosaic virus (OYVMV), indicated that many individual naturally infected plants of cotton and other malvaceous species contained two or three begomovirus sequences. Similarly, sequence differences among overlapping fragments of begomovirus DNA-A, amplified from individual naturally infected plants, indicated much multiple infection in malvaceous and non-malvaceous species. Some cotton plants contained DNA-A sequences typical of begomoviruses from non-malvaceous species, and some non-malvaceous plants contained sequences typical of CLCuV-PK. Some DNA-A sequences were chimaeric; they each included elements typical of different types of CLCuV-PK, or of different malvaceous and/or non-malvaceous begomoviruses. Often an apparent recombination site occurred at the origin of replication. No complete CLCuV-PK DNA-A sequence was found in malvaceous or non-malvaceous species collected in Pakistan outside the area of the cotton leaf curl epidemic but chimaeric sequences, including a part that was typical of CLCuV-PK DNA-A, did occur there. We suggest that recombination among such pre-existing sequences was crucial for the emergence of CLCuV-PK. Recombination, following multiple infection, could also explain the network of relationships among many of the begomoviruses found in the Indian subcontinent, and their evolutionary divergence, as a group, from begomoviruses causing similar diseases in other geographical regions.

Base Sequence↗

PubMed2000

Real-time teleconsultation with high-resolution and large-volume medical images for collaborative healthcare.

Real-time consultation between referring physicians or radiologists with an expert is critical for timely and adequate management of problem cases. During consultation, both sides need to: 1) synchronously manipulate high-resolution digital radiographic images or large volume MR/CT images; 2) perform interpretation interactively; and 3) converse with audio. We present a specifically designed teleconsultation system in a digital imaging and communication in medicine picture archiving and communication systems clinical environment. The system uses bidirectional remote control technology to meet critical teleconsultation application requirements with high-resolution and large-volume medical images operated in a limited-bandwidth network setting. We give the system design and implementation methods, and also describe the teleconsultation procedure and protocol used in this system. Finally, laboratory and clinical evaluation results are discussed.

Delivery of Health Care↗

PubMed2000

Salmonella typhimurium induces apoptosis in human monocyte-derived macrophages.

Salmonella species represent a leading cause of gastroenteritis worldwide. More recently, they have been proposed as putative vaccine delivery vehicles in humans. Oral infection with Salmonella leads to invasion of the intestinal epithelial barrier and subsequent interaction with mucosal macrophages. In this study, we investigated the fate of Salmonella typhimurium-infected human macrophages differentiated from blood monocytes by GM-CSF. Wild type S. typhimurium strain SL1344 induced macrophage surface blebbing and caused the release of host cytoplasmic lactate dehydrogenase beginning 30 min post-infection. Three hours later more than 80% of the macrophages in the culture were killed. In contrast, during the same period, macrophages infected with the non-invasive S. typhimurium strain BJ66 remained viable. Chromatin fragmentation is a hallmark of cells undergoing apoptosis. Using TUNEL analysis, we observed chromatin fragmentation in macrophages infected with SL1344 but not in BJ66 infected cells. Consistent with this observation, we found that pretreatment of human macrophages with an inhibitor of caspase-3, a member of the pro-apoptotic enzyme family shown to be involved in S. typhimurium-induced killing of mouse macrophages, reduced SL1344-mediated cytotoxicity by 40%. Our study provides the first evidence that invasive S. typhimurium induces apoptosis in human macrophages that were differentiated from blood monocytes by GM-CSF, and that cell death is a caspase-dependent phenomenon.

Apoptosis↗

PubMed2000

The role of adaptive immunity in atherosclerosis.

Atherosclerosis is an inflammatory disease induced by a lipid metabolic disturbance at sites of hemodynamic strain in the vasculature. Studies in both man and experimental animal models show an involvement of innate and adaptive immune mechanisms in the disease process. Our recent studies in apoE-knockout mice show that the level of hypercholesterolemia affects the functional properties of the immune response. Modulating immune activity by injections of polyclonal immunoglobulins inhibits disease progression, suggesting that immunomodulation may be useful to treat atherosclerosis. Analysis of T cell receptor (TCR) mRNA in atherosclerotic lesions shows expansions of T cells expressing TCR-V beta 6, a receptor type that is also expressed by T cells recognizing oxidized low density lipoprotein (oxLDL). This suggests that oxLDL is an autoantigen that induces strong, local T cell responses in the plaque. Further characterization of this and other candidate antigens, such as heat shock proteins and macromolecular components of Chlamydia pneumoniae, may provide important information on which specific interference with the disease process could be based.

Animals↗

PubMed2000

PACAP action in nervous system development, regeneration, and neuroblastoma cell proliferation.

Pituitary adenylate cyclase activating peptide (PACAP) may play a role in neurogenesis, nerve injury, and neural tumor growth. A PACAP ligand receptor system functionally coupled to cAMP production was found to be expressed in the embryonic mouse neural tube at the onset of neurogenesis. PACAP was found to inhibit DNA synthesis and antagonize sonic hedgehog signaling in cells isolated from the neural tube, suggesting that PACAP interacts with patterning factors to regulate neurogenesis and phenotypic specification in the developing CNS. PACAP and PACAP receptor (PAC1) mRNA levels were strongly increased and decreased, respectively, in motor neurons in adult rats after facial nerve axotomy, indicating that PACAP may also act in nerve regeneration. Experiments using a neuroblastoma tumor cell line model indicate that PACAP may execute growth-related functions by activating MAP kinase in addition to cAMP-dependent protein kinase A.

Animals↗

PubMed2000

Mechanisms of the proinflammatory response of endothelial cells to Candida albicans infection.

Endothelial cells can influence significantly the host inflammatory response against blood-borne microbial pathogens. Previously, we found that endothelial cells respond to in vitro infection with Candida albicans by secreting interleukin 8 (IL-8) and expressing E-selectin, intercellular adhesion molecule 1 (ICAM-1), and vascular cell adhesion molecule 1 (VCAM-1). We have now examined the mechanisms mediating this endothelial cell response. We determined that C. albicans stimulated endothelial cells to synthesize tumor necrosis factor alpha (TNF-alpha), which in turn induced these infected cells to secrete IL-8 and express E-selectin by an autocrine mechanism. Expression of VCAM-1 was mediated not only by TNF-alpha but also by IL-1alpha and IL-1beta, all of which were synthesized by endothelial cells in response to C. albicans. These three cytokines remained primarily cell associated rather than being secreted. Candidal induction of ICAM-1 expression was independent of TNF-alpha, IL-1alpha, and IL-1beta. These observations demonstrate that different proinflammatory endothelial cell responses to C. albicans are induced by distinct mechanisms. A clear understanding of these mechanisms is important for therapeutically modulating the endothelial cell response to C. albicans and perhaps other opportunistic pathogens that disseminate hematogenously.

Candida albicans↗

PubMed2000

Molecular cloning and expression of a gene encoding Cryptosporidium parvum glycoproteins gp40 and gp15.

Cryptosporidium parvum is a significant cause of diarrheal disease worldwide. The specific molecules that mediate C. parvum-host cell interactions and the molecular mechanisms involved in the pathogenesis of cryptosporidiosis are unknown. In this study we have shown that gp40, a mucin-like glycoprotein, is localized to the surface and apical region of invasive stages of the parasite and is shed from its surface. gp40-specific antibodies neutralize infection in vitro, and native gp40 binds specifically to host cells, implicating this glycoprotein in C. parvum attachment to and invasion of host cells. We have cloned and sequenced a gene designated Cpgp40/15 that encodes gp40 as well as gp15, an antigenically distinct, surface glycoprotein also implicated in C. parvum-host cell interactions. Analysis of the deduced amino acid sequence of the 981-bp Cpgp40/15 revealed the presence of an N-terminal signal peptide, a polyserine domain, multiple predicted O-glycosylation sites, a single potential N-glycosylation site, and a hydrophobic region at the C terminus, a finding consistent with what is required for the addition of a GPI anchor. There is a single copy of Cpgp40/15 in the C. parvum genome, and this gene does not contain introns. Our data indicate that the two Cpgp40/15-encoded proteins, gp40 and gp15, are products of proteolytic cleavage of a 49-kDa precursor protein which is expressed in intracellular stages of the parasite. The surface localization of gp40 and gp15 and their involvement in the host-parasite interaction suggest that either or both of these glycoproteins may serve as effective targets for specific preventive or therapeutic measures for cryptosporidiosis.

Amino Acid Sequence↗

PubMed2000

Phosphorylation of SOX9 by cyclic AMP-dependent protein kinase A enhances SOX9's ability to transactivate a Col2a1 chondrocyte-specific enhancer.

Sox9 is a high-mobility-group domain-containing transcription factor required for chondrocyte differentiation and cartilage formation. We used a yeast two-hybrid method based on Son of Sevenless (SOS) recruitment to screen a chondrocyte cDNA library and found that the catalytic subunit of cyclic AMP (cAMP)-dependent protein kinase A (PKA-Calpha) interacted specifically with SOX9. Next we found that two consensus PKA phosphorylation sites within SOX9 could be phosphorylated by PKA in vitro and that SOX9 could be phosphorylated by PKA-Calpha in vivo. In COS-7 cells cotransfected with PKA-Calpha and SOX9 expression plasmids, PKA enhanced the phosphorylation of wild-type SOX9 but did not affect phosphorylation of a SOX9 protein in which the two PKA phosphorylation sites (S(64) and S(211)) were mutated. Using a phosphospecific antibody that specifically recognized SOX9 phosphorylated at serine 211, one of the two PKA phosphorylation sites, we demonstrated that addition of cAMP to chondrocytes strongly increased the phosphorylation of endogenous Sox9. In addition, immunohistochemistry of mouse embryo hind legs showed that Sox9 phosphorylated at serine 211 was principally localized in the prehypertrophic zone of the growth plate, corresponding to the major site of expression of the parathyroid hormone-related peptide (PTHrP) receptor. Since cAMP has previously been shown to effectively increase the mRNA levels of Col2a1 and other specific markers of chondrocyte differentiation in culture, we then asked whether PKA phosphorylation could modulate the activity of SOX9. Addition of 8-bromo-cAMP to chondrocytes in culture increased the activity of a transiently transfected SOX9-dependent 48-bp Col2a1 chondrocyte-specific enhancer; similarly, cotransfection of PKA-Calpha increased the activity of this enhancer. Mutations of the two PKA phosphorylation consensus sites of SOX9 markedly decreased the PKA-Calpha activation of this enhancer by SOX9. PKA phosphorylation and the mutations in the consensus PKA phosphorylation sites of SOX9 did not alter its nuclear localization. In vitro phosphorylation of SOX9 by PKA resulted in more efficient DNA binding. We conclude that SOX9 is a target of cAMP signaling and that phosphorylation of SOX9 by PKA enhances its transcriptional and DNA-binding activity. Because PTHrP signaling is mediated by cAMP, our results support the hypothesis that Sox9 is a target of PTHrP signaling in the growth plate and that the increased activity of Sox9 might mediate the effect of PTHrP in maintaining the cells as nonhypertrophic chondrocytes.

8-Bromo Cyclic Adenosine Monophosphate↗

PubMed2000

Activation of H(+)-K(+)-ATPase by CO(2) requires a basolateral Ba(2+)-sensitive pathway during K restriction.

We studied the activation of H(+)-K(+)-ATPase by CO(2) in the renal cortical collecting duct (CCD) of K-restricted animals. Exposure of microperfused CCD to 10% CO(2) increased net total CO(2) flux (J(t CO(2))) from 4.9 +/- 2.1 to 14.7 +/- 4 pmol. mm(-1). min(-1) (P < 0. 05), and this effect was blocked by luminal application of the H(+)-K(+)-ATPase inhibitor Sch-28080. In the presence of luminal Ba, a K channel blocker, exposure to CO(2) still stimulated J(t CO(2)) from 6.0 +/- 1.0 to 16.8 +/- 2.8 pmol. mm(-1). min(-1) (P < 0.01), but peritubular application of Ba inhibited the stimulation. CO(2) substantially increased (86)Rb efflux (a K tracer marker) from 93.1 +/- 23.8 to 249 +/- 60.2 nm/s (P < 0.05). These observations suggest that during K restriction 1) the enhanced H(+)-K(+)-ATPase-mediated acidification after exposure to CO(2) is dependent on a basolateral Ba-sensitive mechanism, which is different from the response of rabbits fed a normal-K diet, where activation of the H(+)-K(+)-ATPase by exposure to CO(2) is dependent on an apical Ba-sensitive pathway; and 2) K/Rb absorption via the apical H(+)-K(+)-ATPase exits through a basolateral Ba-sensitive pathway. Together, these data are consistent with the hypothesis of cooperation between H(+)-K(+)-ATPase-mediated acidification and K exit pathways in the CCD that regulate K homeostasis.

Animals↗

PubMed2000

Brief and short-term corticofugal modulation of subcortical auditory responses in the big brown bat, Eptesicus fuscus.

Recent studies show that the auditory corticofugal system modulates and improves ongoing signal processing and reorganizes frequency map according to auditory experience in the central nucleus of bat inferior colliculus. However, whether all corticofugally affected collicular neurons are involved in both types of modulation has not been determined. In this study, we demonstrate that one group (51%) of collicular neurons participates only in corticofugal modulation of ongoing signal processing, while a second group (49%) of collicular neurons participates in both modulation of ongoing signal processing and in reorganization of the auditory system.

Acoustic Stimulation↗

PubMed2000

Expression of Foxb1 reveals two strategies for the formation of nuclei in the developing ventral diencephalon.

Fork head b1 (Foxb1; also called Fkh5, HFH-e5.1, Mf3) is a winged helix transcription factor gene whose widespread early expression in the developing neural tube is soon restricted to the ventral and caudal diencephalon. During diencephalic neurogenesis, Foxb1 is expressed in one patch of neuroepithelium comprising a large mammillary portion and a smaller tuberal portion. The labeled cells coming from this patch contribute to nuclear formation by means of two different strategies: (1) caudally, the young neurons aggregate and settle immediately, giving rise to the nuclei of the mammillary body; (2) rostrally, the young neurons separate from the neuroepithelium forming a trail of cells which spans the mantle layer mediolaterally and which will give rise to two separate cell groups (the dorsal premammillary and part of the lateral hypothalamic area). Our results show the elaborate, regionalized histogenetic mechanisms necessary for the differentiation of the caudal diencephalon; moreover, they suggest that specifically labeled populations, arising from specifically labeled neuroepithelial patches and giving place to specific brain nuclei could be a common mechanism to build complex, nonlaminar regions of the forebrain.

Animals↗

PubMed2000

Oligoclonal T cell expansions in atherosclerotic lesions of apolipoprotein E-deficient mice.

T cells are present in atherosclerotic lesions at all stages of development. They exhibit activation markers and are particularly prominent at sites of plaque rupture. This suggests that T-cell-mediated immune responses are involved in the pathogenesis of atherosclerosis. Antigen-specific T cells reactive with oxidized lipoproteins and heat shock proteins have been isolated from plaques, indicating that local activation and clonal expansion might occur. To analyze different stages of atherosclerosis, we have used a murine model. Targeted deletion of the apolipoprotein E gene results in severe hypercholesterolemia and spontaneous atherosclerosis, with lesions containing large numbers of T cells and macrophages. We have analyzed mRNA for T-cell antigen receptors (TCRs) from aortic fatty streaks, early fibrofatty plaques, and advanced fibrofatty plaques of such mice. Polymerase chain reaction amplification of complementarity-determining region 3 (CDR3 region) of TCRs was followed by spectratyping of fragment lengths. This analysis detected all types of variable (V) segments with a gaussian distribution of CDR3 in lymph nodes. In contrast, a restricted heterogeneity was found in atherosclerotic lesions, with expansion of a limited set of Vbeta and Valpha segments and a monotypic or oligotypic CDR3 spectrum in each lesion. Vbeta6 was expressed in all lesions; Vbeta5.2, Vbeta16, Valpha34s, and Valpha9, in the majority of lesions; and Vbeta6, Vbeta5.2, and Valpha34S, in lesions at all 3 stages of development. The strongly skewed pattern of the CDR3 region in the TCR is indicative of oligoclonal expansions of T cells and suggests the occurrence of antigen-driven T-cell proliferation in atherosclerosis.

Animals↗

PubMed2000

A critical role for neutrophil elastase in experimental bullous pemphigoid.

Bullous pemphigoid (BP) is an autoimmune skin disease characterized by subepidermal blisters and autoantibodies against 2 hemidesmosome-associated proteins, BP180 and BP230. The immunopathologic features of BP can be reproduced in mice by passive transfer of anti-BP180 antibodies. Lesion formation in this animal model depends upon complement activation and neutrophil recruitment. In the present study, we investigated the role of neutrophil elastase (NE) in antibody-induced blister formation in experimental BP. Abnormally high levels of caseinolytic activity, consistent with NE, were detected in extracts of lesional skin and blister fluid of mice injected with anti-BP180 IgG. The pathogenic anti-BP180 IgG failed to induce subepidermal blistering in NE-null (NE(-/-)) mutant mice. NE(-/-) mice reconstituted with neutrophils from wild-type mice became susceptible to experimental BP. Wild-type mice given NE inhibitors (alpha1-proteinase inhibitor and Me-O-Suc-Ala-Ala-Pro-Val-CH(2)Cl), but not mice given cathepsin G/chymase inhibitors (alpha1-antichymotrypsin or Z-Gly-Leu-Phe-CH(2)Cl), were resistant to the pathogenic activity of anti-BP180 antibodies. Incubation of murine skin with NE induced BP-like epidermal-dermal detachment. Finally, NE cleaved BP180 in vitro and in vivo. These results implicate NE directly in the dermal-epidermal cleavage induced by anti-BP180 antibodies in the experimental BP model.

Animals↗

PubMed2000

Expression of cyclin-dependent kinase inhibitors in epiphyseal chondrocytes induced to terminally differentiate with thyroid hormone.

A growing body of evidence suggests that systemic hormones and peptide growth factors may exert their effects on cell growth and differentiation in part through regulation of the cell division cycle. We hypothesized that thyroid hormone regulates terminal differentiation of growth plate chondrocytes in part through controlling cell cycle progression at the G1/S restriction point. Our results support this hypothesis by demonstrating that treatment of epiphyseal chondrocytes with thyroid hormone under chemically defined conditions results in the arrest of DNA synthesis and the onset of terminal differentiation, indicating that thyroid hormone is one factor capable of regulating the transition between cell growth and differentiation in these cells. This terminal differentiation process is associated with induction of the cyclin/cyclin-dependent kinase inhibitors p21(cip-1 waf-1) and p27kip1, suggesting that thyroid hormone may regulate terminal differentiation in part by arresting cell cycle progression through induction of cyclin-dependent kinase inhibitors.

Animals↗

PubMed2000

Characterization and messenger ribonucleic acid distribution of a cloned pituitary adenylate cyclase-activating polypeptide type I receptor in the frog Xenopus laevis brain.

Pituitary adenylate cyclase-activating polypeptide (PACAP) has been found to modulate neuroendocrine functions in the frog brain and pituitary, but the nucleotide sequence and brain distribution of messenger RNA (mRNA) for the selective type I receptor for PACAP (PAC1) in the frog are still unknown. Here, we report the isolation and characterization of a PAC1 receptor complementary DNA (cDNA) clone from a frog (Xenopus laevis) tadpole brain cDNA library. This cDNA encoded a 466-amino acid protein that has 74% homology with human PAC1 receptor and 48% homology to the frog vasoactive intestinal peptide/PACAP receptor. Injection of in vitro synthesized mRNA of the cloned cDNA into Xenopus oocytes resulted in expression of selective high affinity PACAP receptors (Kd = 47 pM). IC50 values for PACAP-38, PACAP-27, and VIP were 27 pM, 110 pM and >1 microM, respectively. These results indicated that the cloned cDNA represents a Xenopus PACAP-preferring PAC1 receptor. Northern hybridization revealed that PAC1 receptor mRNA was present at high levels in the brain. In situ hybridization showed that the PAC1 receptor gene was expressed highly in the pallium, preoptic nucleus, and nucleus of cerebellum, and moderately in the Purkinje cell layer of the cerebellum. Moderate PAC1 receptor mRNA signals were detected in the distal lobe of the pituitary. A knowledge of the molecular structure and expression pattern of the PAC1 receptor will facilitate further investigation of the physiological roles of PAC1 receptor in the frog brain.

Amino Acid Sequence↗

PubMed2000

Molecular cloning of growth hormone-releasing hormone/pituitary adenylyl cyclase-activating polypeptide in the frog Xenopus laevis: brain distribution and regulation after castration.

Pituitary adenylyl cyclase-activating peptide (PACAP) appears to regulate several neuroendocrine functions in the frog, but its messenger RNA (mRNA) structure and brain distribution are unknown. To understand the potential role of PACAP in the male frog hypothalamic-pituitary-gonadal axis, we cloned the frog Xenopus laevis PACAP mRNA and determined its distribution in the brain. We then analyzed the castration-induced alterations of mRNA expression for PACAP and its selective type I receptor (PAC1) in the hypothalamic anterior preoptic area, a region known to regulate reproductive function. The PACAP mRNA encodes a peptide precursor predicted to give rise to both GH-releasing hormone and PACAP. The deduced peptide sequence of PACAP-38 was nearly identical to that of human PACAP with one amino acid substitution. Abundant PACAP mRNA was detected in the brain, but not several other tissues, including the testis. In situ hybridization revealed strong expression of the PACAP gene in the dorsal pallium, ventral hypothalamus, and nuclei of cerebellum. PACAP mRNA signals were weak to moderate in the hypothalamic anterior preoptic area and were absent in the pituitary. Castration induced an increase in the expression of PACAP and PAC1 receptor mRNAs in the hypothalamic anterior preoptic area after 3 days. Replacement with testosterone prevented the castration-induced changes. These results provide a molecular basis for studying the physiological functions of PACAP in frog brain and suggest that PACAP may be involved in the feedback regulation of hypothalamic-pituitary-gonadal axis.

Amino Acid Sequence↗

PubMed2000

Winged helix transcription factor Foxb1 is essential for access of mammillothalamic axons to the thalamus.

Our aim was to study the mechanisms of brain histogenesis. As a model, we have used the role of winged helix transcription factor gene Foxb1 in the emergence of a very specific morphological trait of the diencephalon, the mammillary axonal complex. Foxb1 is expressed in a large hypothalamic neuronal group (the mammillary body), which gives origin to a major axonal bundle with branches to thalamus, tectum and tegmentum. We have generated mice carrying a targeted mutation of Foxb1 plus the tau-lacZ reporter. In these mutants, a subpopulation of dorsal thalamic ventricular cells "thalamic palisade" show abnormal persistence of Foxb1 transcriptional activity; the thalamic branch of the mammillary axonal complex is not able to grow past these cells and enter the thalamus. The other two branches of the mammillary axonal complex (to tectum and tegmentum) are unaffected by the mutation. Most of the neurons that originate the mammillothalamic axons suffer apoptosis after navigational failure. Analysis of chimeric brains with wild-type and Foxb1 mutant cells suggests that correct expression of Foxb1 in the thalamic palisade is sufficient to rescue the normal phenotype. Our results indicate that Foxb1 is essential for diencephalic histogenesis and that it exerts its effects by controlling access to the target by one particular axonal branch.

Animals↗

PubMed2000

BMP-2/ALK3 and HGF signal in parallel to regulate renal collecting duct morphogenesis.

Bone morphogenetic protein (BMP)-2 and hepatocyte growth factor (HGF) exert antagonistic effects on renal collecting duct formation during embryogenesis. A current model proposes HGF inhibits BMP-2 signaling at the level of Smad1 in a common target cell. Here, we show that BMP-2 and HGF control collecting duct formation via parallel pathways. We examined the interactions between BMP-2 and HGF in the mIMCD-3 model of collecting duct morphogenesis. During tubule formation, HGF rescued the inhibitory effects of BMP-2 and of a constitutive active form of the BMP-2 receptor, ALK3, stably expressed in mIMCD-3 cells. To determine whether the effect of HGF occurs through known mediators which act downstream of the BMP-2/ALK3 complex, we examined the effect of HGF on BMP-2-induced Smad1 phosphorylation, Smad1/Smad4 complex formation, and Smad1 nuclear translocation. Neither HGF nor other receptor tyrosine kinase ligands (EGF, FGF-4) induced phosphorylation of endogenous Smad1 in mIMCD-3 cells or in Mv1Lu, MC3T3-E1 or P19 cells. Furthermore, none of these ligands blocked induction of the BMP-responsive promoter, Tlx2. Thus, HGF overcomes the inhibitory effects of BMP-2 on collecting duct morphogenesis without interrupting any of the known signaling events in the BMP-2 dependent Smad1 signaling pathway. We conclude that BMP-2/ALK3 and HGF function to control parallel pathways downstream of their respective cell surface receptors. Integration of these signals likely occurs at the level of transcriptional or post-transcriptional events.

Activin Receptors↗