scholarly journals Chondrodysplasia in transgenic mice harboring a 15-amino acid deletion in the triple helical domain of pro alpha 1(II) collagen chain.

1992 ◽  
Vol 118 (1) ◽  
pp. 203-212 ◽  
Author(s):  
M Metsäranta ◽  
S Garofalo ◽  
G Decker ◽  
M Rintala ◽  
B de Crombrugghe ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Endochondral Ossification ◽  
Electron Microscopic Examination ◽  
Type Ii Collagen ◽  
Dominant Negative ◽  
Collagen Molecule ◽  
Type Ii ◽  
Electron Microscopic ◽  
Dominant Negative Mutation ◽  
Collagen Chain

We have generated transgenic mice by microinjection of a 39-kb mouse pro alpha 1(II) collagen gene construct containing a deletion of exon 7 and intron 7. This mutation was expected to disturb the assembly and processing of the homotrimeric type II collagen molecule in cartilage. Expression of transgene mRNA at levels equivalent or higher than the endogenous mRNA in the offspring of two founder animals resulted in a severe chondrodysplastic phenotype with short limbs, hypoplastic thorax, abnormal craniofacial development, and other skeletal deformities. The affected pups died at birth due to respiratory distress. Light microscopy of epiphyseal growth plates of transgenic pups demonstrated a marked reduction in cartilaginous extracellular matrix and disruption of the normal organization of the growth plate. The zone of proliferating chondrocytes was greatly reduced whereas the zone of hypertrophic chondrocytes was markedly increased extending deep into the diaphysis suggestive of a defect in endochondral ossification. Electron microscopic examination revealed chondrocytes with extended RER, a very severe reduction in the amount of cartilage collagen fibrils, and abnormalities in their structure. We postulate that the deletion in the alpha 1(II) collagen acts as a dominant negative mutation disrupting the assembly and secretion of type II collagen molecules. The consequences of the mutation include interference with normal endochondral ossification. These mice constitute a valuable model to study the mechanisms underlying human chondrodysplasias and normal bone formation.

scholarly journals Skeletal Malformations Caused by Overexpression of Cbfa1 or Its Dominant Negative Form in Chondrocytes

2001 ◽  
Vol 153 (1) ◽  
pp. 87-100 ◽  
Author(s):  
Chisato Ueta ◽  
Masahiro Iwamoto ◽  
Naoko Kanatani ◽  
Carolina Yoshida ◽  
Yang Liu ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Endochondral Ossification ◽  
Skeletal Development ◽  
Type Ii Collagen ◽  
Dominant Negative ◽  
Chondrocyte Maturation ◽  
Skeletal Malformations ◽  
Dominant Negative Form ◽  
Cellular Phenotypes

During skeletogenesis, cartilage develops to either permanent cartilage that persists through life or transient cartilage that is eventually replaced by bone. However, the mechanism by which cartilage phenotype is specified remains unclarified. Core binding factor α1 (Cbfa1) is an essential transcription factor for osteoblast differentiation and bone formation and has the ability to stimulate chondrocyte maturation in vitro. To understand the roles of Cbfa1 in chondrocytes during skeletal development, we generated transgenic mice that overexpress Cbfa1 or a dominant negative (DN)-Cbfa1 in chondrocytes under the control of a type II collagen promoter/enhancer. Both types of transgenic mice displayed dwarfism and skeletal malformations, which, however, resulted from opposite cellular phenotypes. Cbfa1 overexpression caused acceleration of endochondral ossification due to precocious chondrocyte maturation, whereas overexpression of DN-Cbfa1 suppressed maturation and delayed endochondral ossification. In addition, Cbfa1 transgenic mice failed to form most of their joints and permanent cartilage entered the endochondral pathway, whereas most chondrocytes in DN-Cbfa1 transgenic mice retained a marker for permanent cartilage. These data show that temporally and spatially regulated expression of Cbfa1 in chondrocytes is required for skeletogenesis, including formation of joints, permanent cartilages, and endochondral bones.

scholarly journals Cellular Werner Phenotypes in Mice Expressing a Putative Dominant-Negative Human WRN Gene

Genetics ◽  
2000 ◽  
Vol 154 (1) ◽  
pp. 357-362
Author(s):  
Lan Wang ◽  
Charles E Ogburn ◽  
Carol B Ware ◽  
Warren C Ladiges ◽  
Hagop Youssoufian ◽  
...  
Keyword(s):  
Mouse Model ◽  
Transgenic Mice ◽  
Werner Syndrome ◽  
Dominant Negative ◽  
Dominant Negative Mutation ◽  
Fibroblast Cultures ◽  
Age Related

Abstract Mutations at the Werner helicase locus (WRN) are responsible for the Werner syndrome (WS). WS patients prematurely develop an aged appearance and various age-related disorders. We have generated transgenic mice expressing human WRN with a putative dominant-negative mutation (K577M-WRN). Primary tail fibroblast cultures from K577M-WRN mice showed three characteristics of WS cells: hypersensitivity to 4-nitroquinoline-1-oxide (4NQO), reduced replicative potential, and reduced expression of the endogenous WRN protein. These data suggest that K577M-WRN mice may provide a novel mouse model for the WS.

scholarly journals Osteoarthritis-like lesions in transgenic mice harboring a small deletion mutation in type II collagen gene

2000 ◽  
Vol 8 (4) ◽  
pp. 248-257 ◽  
Author(s):  
A.-M.K Säämänen ◽  
H.J Salminen ◽  
P.B Dean ◽  
B De Crombrugghe ◽  
E.I Vuorio ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Type Ii Collagen ◽  
Deletion Mutation ◽  
Collagen Gene ◽  
Type Ii ◽  
Small Deletion

Skeletal development in transgenic mice expressing a mutation at Gly574Ser of type II collagen

1997 ◽  
Vol 208 (2) ◽  
pp. 170-177 ◽  
Author(s):  
B. Kerry Maddox ◽  
Silvio Garofalo ◽  
Chad Smith ◽  
Douglas R. Keene ◽  
William A. Horton
Keyword(s):  
Transgenic Mice ◽  
Skeletal Development ◽  
Type Ii Collagen ◽  
Type Ii

scholarly journals Immunoelectron microscopic studies of type X collagen in endochondral ossification.

1989 ◽  
Vol 109 (5) ◽  
pp. 2547-2554 ◽  
Author(s):  
A R Poole ◽  
I Pidoux
Keyword(s):  
Monoclonal Antibody ◽  
Endochondral Ossification ◽  
Type Ii Collagen ◽  
Matrix Vesicles ◽  
Type Ii ◽  
Type X Collagen ◽  
Immunogold Staining ◽  
Proliferative Zone ◽  
Microscopic Studies ◽  
Tibial Growth Plate

Immunofluorescence and immunoelectron microscopy were used in conjunction with a monoclonal antibody to investigate the localization of type X collagen in the proximal tibial growth plate of 7-d-old chicks. This molecule was detected throughout the hypertrophic zone first appearing when chondrocytes exhibited hypertrophy: it was absent from the proliferative zone. Type X collagen was primarily associated with type II collagen fibrils as demonstrated by immunogold staining. Type X collagen was not concentrated in the focal calcification sites nor was it associated with matrix vesicles. These observations suggest that type X collagen may play a role other than that directly related to the nucleation of calcification.

scholarly journals Localization of an arthritogenic epitope to a fragment of the type II collagen molecule.

Ensho ◽  
1986 ◽  
Vol 6 (4) ◽  
pp. 351-356
Author(s):  
Kuniaki Terato ◽  
Yasunori Shimozuru ◽  
Karen A. Hasty ◽  
Michael A. Cremer ◽  
John M. Stuart ◽  
...  
Keyword(s):  
Type Ii Collagen ◽  
Collagen Molecule ◽  
Type Ii

Urethane-induced Mammary Carcinogenesis Susceptibility in Transgenic Mice Expressing a Dominant-negative TGF-β Type II Receptor

2020 ◽  
Vol 40 (5) ◽  
pp. 2687-2694
Author(s):  
MASA-AKI SHIBATA ◽  
EIKO SHIBATA ◽  
JUNJI MORIMOTO ◽  
YOICHI KONDO
Keyword(s):  
Transgenic Mice ◽  
Mammary Carcinogenesis ◽  
Dominant Negative ◽  
Type Ii

Differential co-expression of long and short form type IX collagen transcripts during avian limb chondrogenesis in ovo

Development ◽  
1992 ◽  
Vol 115 (1) ◽  
pp. 169-179
Author(s):  
R.E. Swiderski ◽  
M. Solursh
Keyword(s):  
Core Protein ◽  
Short Form ◽  
Marker Gene ◽  
Type Ii Collagen ◽  
Marker Genes ◽  
Type Ii ◽  
Amino Terminal ◽  
Collagen Mrna ◽  
Long Form ◽  
Collagen Chain

Using RNA blot analysis of developmentally staged avian limb buds, we demonstrate that transcripts of several cartilage marker genes appear in limb tissue prior to overt chondrogenesis. Type II collagen mRNA, cartilage proteoglycan core protein mRNA, alpha 2(IX) collagen mRNA, and transcripts of the short form alpha 1(IX) collagen chain derived from the downstream promoter are co-expressed in limb tissue approximately 24–36 hours before the appearance of the respective polypeptides in differentiating cartilagenous tissue. Transcripts of the long form alpha 1(IX) collagen chain derived from the upstream promoter appear somewhat later in development; nearly coincident with the immunolocalization of type IX collagen in the cartilage elements of the limb. The spatial distribution of type II and type IX collagen transcripts was analyzed by in situ hybridization. Type II collagen and the long form alpha 1(IX) collagen transcripts co-localized in the chondrogenic elements of the developing forelimb. In contrast, short form alpha 1(IX) collagen transcripts which lack the 5′ region encoding the NC4 globular amino-terminal domain were distributed throughout the non-chondrogenic, non-myogenic mesenchymal regions of the limb and were not detectable above background levels in the limb chondrogenic elements. The precocious appearance of several cartilage marker gene transcripts prior to chondrogenesis suggests that multiple levels of gene regulation including alternative promoter use, alternative RNA splicing, alternative polyadenylation, and other post-transcriptional as well as translational mechanisms are active prior to, and during avian limb chondrogenesis.

Absence of proximal duct apoptosis in the ventral prostate of transgenic mice carrying the C3(1)-TGF-? type II dominant negative receptor

The Prostate ◽  
2000 ◽  
Vol 43 (2) ◽  
pp. 118-124 ◽  
Author(s):  
Shilajit D. Kundu ◽  
Isaac Y. Kim ◽  
Tony Yang ◽  
Lynn Doglio ◽  
Sharon Lang ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Dominant Negative ◽  
Ventral Prostate ◽  
Type Ii
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