scholarly journals Expression of a Constitutively Active Type I BMP Receptor Using a Retroviral Vector Promotes the Development of Adrenergic Cells in Neural Crest Cultures

1998 ◽  
Vol 196 (1) ◽  
pp. 107-118 ◽  
Author(s):  
J.E. Varley ◽  
C.E. McPherson ◽  
H. Zou ◽  
L. Niswander ◽  
G.D. Maxwell
Keyword(s):  
Neural Crest ◽  
Retroviral Vector ◽  
Type I ◽  
Active Type ◽  
Bmp Receptor ◽  
Constitutively Active

scholarly journals Cercosporamide inhibits bone morphogenetic protein receptor type I kinase activity in zebrafish

2020 ◽  
Vol 13 (9) ◽  
pp. dmm045971 ◽  
Author(s):  
Jelmer Hoeksma ◽  
Gerard C. M. van der Zon ◽  
Peter ten Dijke ◽  
Jeroen den Hertog
Keyword(s):  
Bone Morphogenetic Protein ◽  
Mammalian Cells ◽  
Kinase Activity ◽  
Fibrodysplasia Ossificans Progressiva ◽  
Type I ◽  
Developmental Defects ◽  
Bone Morphogenetic Protein Receptor ◽  
Protein Receptor ◽  
Morphogenetic Protein ◽  
Constitutively Active

ABSTRACTZebrafish models are well-established tools for investigating the underlying mechanisms of diseases. Here, we identified cercosporamide, a metabolite from the fungus Ascochyta aquiliqiae, as a potent bone morphogenetic protein receptor (BMPR) type I kinase inhibitor through a zebrafish embryo phenotypic screen. The developmental defects in zebrafish, including lack of the ventral fin, induced by cercosporamide were strikingly similar to the phenotypes caused by renowned small-molecule BMPR type I kinase inhibitors and inactivating mutations in zebrafish BMPRs. In mammalian cell-based assays, cercosporamide blocked BMP/SMAD-dependent transcriptional reporter activity and BMP-induced SMAD1/5-phosphorylation. Biochemical assays with a panel of purified recombinant kinases demonstrated that cercosporamide directly inhibited kinase activity of type I BMPRs [also called activin receptor-like kinases (ALKs)]. In mammalian cells, cercosporamide selectively inhibited constitutively active BMPR type I-induced SMAD1/5 phosphorylation. Importantly, cercosporamide rescued the developmental defects caused by constitutively active Alk2 in zebrafish embryos. We believe that cercosporamide could be the first of a new class of molecules with potential to be developed further for clinical use against diseases that are causally linked to overactivation of BMPR signaling, including fibrodysplasia ossificans progressiva and diffuse intrinsic pontine glioma.This article has an associated First Person interview with the first author of the paper.

scholarly journals Differential Roles for Bone Morphogenetic Protein (BMP) Receptor Type IB and IA in Differentiation and Specification of Mesenchymal Precursor Cells to Osteoblast and Adipocyte Lineages

1998 ◽  
Vol 142 (1) ◽  
pp. 295-305 ◽  
Author(s):  
D. Chen ◽  
X. Ji ◽  
M.A. Harris ◽  
J.Q. Feng ◽  
G. Karsenty ◽  
...  
Keyword(s):  
Osteoblast Differentiation ◽  
Adipocyte Differentiation ◽  
Bone Matrix ◽  
Culture Conditions ◽  
Bmp Receptor ◽  
Bmp Receptors ◽  
Type Ia ◽  
Mineralized Bone Matrix ◽  
Mesenchymal Precursor ◽  
Constitutively Active

Cumulative evidence indicates that osteoblasts and adipocytes share a common mesenchymal precursor and that bone morphogenetic proteins (BMPs) can induce both osteoblast and adipocyte differentiation of this precursor. In the present study, we investigated the roles of BMP receptors in differentiation along these separate lineages using a well-characterized clonal cell line, 2T3, derived from the mouse calvariae. BMP-2 induced 2T3 cells to differentiate into mature osteoblasts or adipocytes depending upon culture conditions. To test the specific roles of the type IA and IB BMP receptor components, truncated and constitutively active type IA and IB BMP receptor cDNAs were stably expressed in these cells. Overexpression of truncated type IB BMP receptor (trBMPR-IB) in 2T3 cells completely blocked BMP-2–induced osteoblast differentiation and mineralized bone matrix formation. Expression of trBMPR-IB also blocked mRNA expression of the osteoblast specific transcription factor, Osf2/ Cbfa1, and the osteoblast differentiation-related genes, alkaline phosphatase (ALP) and osteocalcin (OC). BMP-2–induced ALP activity could be rescued by transfection of wild-type (wt) BMPR-IB into 2T3 clones containing trBMPR-IB. Expression of a constitutively active BMPR-IB (caBMPR-IB) induced formation of mineralized bone matrix by 2T3 cells without addition of BMP-2. In contrast, overexpression of trBMPR-IA blocked adipocyte differentiation and expression of caBMPR-IA induced adipocyte formation in 2T3 cells. Expression of the adipocyte differentiation-related genes, adipsin and PPARγ, correlated with the distinct phenotypic changes found after overexpression of the appropriate mutant receptors. These results demonstrate that type IB and IA BMP receptors transmit different signals to bone-derived mesenchymal progenitors and play critical roles in both the specification and differentiation of osteoblasts and adipocytes.

scholarly journals Neural crest cell migration: requirements for exogenous fibronectin and high cell density.

1983 ◽  
Vol 96 (2) ◽  
pp. 462-473 ◽  
Author(s):  
R A Rovasio ◽  
A Delouvee ◽  
K M Yamada ◽  
R Timpl ◽  
J P Thiery
Keyword(s):  
Cell Adhesion ◽  
Neural Crest ◽  
Type I Collagen ◽  
Neural Crest Cell ◽  
Neural Crest Cells ◽  
Type I ◽  
Cell Adhesion And Migration ◽  
And Migration ◽  
Crest Cell

Cells of the neural crest participate in a major class of cell migratory events during embryonic development. From indirect evidence, it has been suggested that fibronectin (FN) might be involved in these events. We have directly tested the role of FN in neural crest cell adhesion and migration using several in vitro model systems. Avian trunk neural crest cells adhered readily to purified plasma FN substrates and to extracellular matrices containing cellular FN. Their adhesion was inhibited by antibodies to a cell-binding fragment of FN. In contrast, these cells did not adhere to glass, type I collagen, or to bovine serum albumin in the absence of FN. Neural crest cell adhesion to laminin (LN) was significantly less than to FN; however, culturing of crest cells under conditions producing an epithelioid phenotype resulted in cells that could bind equally as well to LN as to FN. The migration of neural crest cells appeared to depend on both the substrate and the extent of cell interactions. Cells migrated substantially more rapidly on FN than on LN or type I collagen substrates; if provided a choice between stripes of FN and glass or LN, cells migrated preferentially on the FN. Migration was inhibited by antibodies against the cell-binding region of FN, and the inhibition could be reversed by a subsequent addition of exogenous FN. However, the migration on FN was random and displayed little persistence of direction unless cells were at high densities that permitted frequent contacts. The in vitro rate of migration of cells on FN-containing matrices was 50 microns/h, similar to their migration rates along the narrow regions of FN-containing extracellular matrix in migratory pathways in vivo. These results indicate that FN is important for neural crest cell adhesion and migration and that the high cell densities of neural crest cells in the transient, narrow migratory pathways found in the embryo are necessary for effective directional migration.

1291 ANALYSIS OF CIRCULATING CD4+ AND CD8+ T MEMORY SUBSETS IN ACTIVE TYPE I AUTOIMMUNE HEPATITIS AND DURING ITS BIOCHEMICAL REMISSION

2011 ◽  
Vol 54 ◽  
pp. S509
Author(s):  
N.E. Ferreyra Solari ◽  
D. Levi ◽  
A. Villamil ◽  
P. Baz ◽  
A. Billordo ◽  
...  
Keyword(s):  
Autoimmune Hepatitis ◽  
Type I ◽  
Active Type ◽  
Biochemical Remission

Otopathology in a Case of Type I Waardenburg's Syndrome

2001 ◽  
Vol 110 (9) ◽  
pp. 875-882 ◽  
Author(s):  
Saumil N. Merchant ◽  
Michael J. McKenna ◽  
Aubrey Milunsky ◽  
Clinton T. Baldwin ◽  
Joseph B. Nadol
Keyword(s):  
Neural Crest ◽  
Ganglion Cells ◽  
Stria Vascularis ◽  
Spiral Ganglion ◽  
Low Frequency ◽  
Tectorial Membrane ◽  
Type I ◽  
Dark Cells ◽  
Pathological Alteration ◽  
Microscopic Studies

We report a case of type I Waardenburg's syndrome that provides insight into the etiopathogenesis of sensorineural hearing loss (SNHL) in this syndrome. The subject, a 76-year-old woman with type I Waardenburg's syndrome (dystopia canthorum, heterochromia irides, and white hair), had congenital low-frequency SNHL in her right ear only, which had remained relatively stable throughout her life. Blood leukocyte DNA studies revealed a PAX-3 mutation with a 1 base pair C-to-A substitution in exon 5 at base 602. Light microscopic studies of the right cochlea showed intact neurosensory structures in only the lower basal turn, with the remainder of the cochlea showing absence of melanocytes, absence of stria vascularis, missing hair cells, dysmorphogenesis of the tectorial membrane, and lack of peripheral processes of the spiral ganglion cells. There was pathological alteration of the vestibular dark cells with marked reduction of melanocytes associated with these dark cells. The left inner ear was normal, with a full complement of neurosensory structures, including melanocytes. Because the PAX-3 gene is involved in neural crest development and melanocytes migrate from the neural crest to the ear, the findings in this case are consistent with the hypothesis that defective melanocyte migration or defective melanocyte function results in defective development of the stria vascularis (and perhaps other structures of the ear). leading to SNHL.

scholarly journals The ALK-2 and ALK-4 activin receptors transduce distinct mesoderm-inducing signals during early Xenopus development but do not co-operate to establish thresholds

Development ◽  
1997 ◽  
Vol 124 (19) ◽  
pp. 3797-3804 ◽  
Author(s):  
N.A. Armes ◽  
J.C. Smith
Keyword(s):  
Cell Types ◽  
Type I ◽  
Cell Stage ◽  
Mesodermal Cell ◽  
Threshold Phenomenon ◽  
Dose Dependent Fashion ◽  
High Concentrations ◽  
Dose Dependent ◽  
Activin Receptors ◽  
Constitutively Active

The TGFbeta family member activin induces different mesodermal cell types in a dose-dependent fashion in the Xenopus animal cap assay. High concentrations of activin induce dorsal and anterior cell types such as notochord and muscle, while low concentrations induce ventral and posterior tissues such as mesenchyme and mesothelium. In this paper we investigate whether this threshold phenomenon involves the differential effects of the two type I activin receptors ALK-2 and ALK-4. Injection of RNA encoding constitutively active forms of the receptors (here designated ALK-2* and ALK-4*) reveals that ALK-4* strongly induces the more posterior mesodermal marker Xbra and the dorsoanterior marker goosecoid in animal cap explants. Maximal levels of Xbra expression are attained using lower concentrations of RNA than are required for the strongest activation of goosecoid, and at the highest doses of ALK-4*, levels of Xbra transcription decrease, as is seen with high concentrations of activin. By contrast, the ALK-2* receptor activates Xbra but fails to induce goosecoid to significant levels. Analysis at later stages reveals that ALK-4* signalling induces the formation of a variety of mesodermal derivatives, including dorsal cell types, in a dose-dependent fashion, and that high levels also induce endoderm. By contrast, the ALK-2* receptor induces only ventral mesodermal markers. Consistent with these observations, ALK-4* is capable of inducing a secondary axis when injected into the ventral side of 32-cell stage embryos whilst ALK-2* cannot. Co-injection of RNAs encoding constitutively active forms of both receptors reveals that ventralising signals from ALK-2* antagonise the dorsal mesoderm-inducing signal derived from ALK-4*, suggesting that the two receptors use distinct and interfering signalling pathways. Together, these results show that although ALK-2* and ALK-4* transduce distinct signals, the threshold responses characteristic of activin cannot be due to interactions between these two pathways; rather, thresholds can be established by ALK-4* alone. Furthermore, the effects of ALK-2* signalling are at odds with it behaving as an activin receptor in the early Xenopus embryo.

scholarly journals Selective inhibition of human T-lymphotropic virus type I-transformed human T-cell growth by a tax-targeted conditionally cytotoxic recombinant retrovirus

Blood ◽  
1994 ◽  
Vol 84 (8) ◽  
pp. 2591-2596 ◽  
Author(s):  
M Fujita ◽  
K Murata ◽  
H Shiku
Keyword(s):  
Gene Therapy ◽  
T Cell ◽  
Cell Lines ◽  
Virus Type ◽  
Retroviral Vector ◽  
Leukemic Cells ◽  
Type I ◽  
Retroviral Infection ◽  
T Lymphotropic Virus ◽  
Human T Cell

Abstract Adult T-cell leukemia (ATL), a disorder associated with high mortality rates, arises from human T-lymphotropic virus type I (HTLV-I)-infected CD4+ T cells. We designed a retroviral vector-based gene therapy approach to ATL. The long terminal repeat (LTR) of HTLV-I is transactivated by the viral tax protein. We constructed a hybrid gene consisting of herpes simplex virus thymidine kinase (HSV TK) under the control of the HTLV-I LTR and inserted it into a retroviral vector. When HTLV-I-transformed and tax-expressing human T-cell lines were infected with this recombinant retrovirus (LNLTK alpha virus), they expressed high levels of HSV TK and exhibited increased sensitivity to acyclovir, a nucleoside analog that is converted to the toxic anabolite after phosphorylation by the HSV TK. On the other hand, the retroviral infection had little effect on acyclovir-induced cytotoxicity in HTLV-I- negative human hematopoietic cell lines. Our data may provide the prospect of the gene therapy for ATL by tax-targeted selective elimination of leukemic cells.

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