Biomedical subjects

A Lawshé

Publications and source records attributed to A Lawshé.

5 recordsLinked to original sources

PubMed1998

MMTV-Fgf8 transgenic mice develop mammary and salivary gland neoplasia and ovarian stromal hyperplasia.

Prior studies have identified Fibroblast Growth Factor-8 (Fgf8) as a possible proto-oncogene in mouse mammary tumorigenesis. We now report on the generation of two types of Fgf8 transgenic mice that each utilize the mouse mammary tumor virus (MMTV) promoter. The first transgene (MMTV-Fgf8b) results in the overexpression of the FGF8b isoform exclusively. Male and female MMTV-Fgf8b transgenic mice are viable and fertile. RNA for FGF8b is detected in mammary gland and salivary gland tissues of transgenic mice by Northern blot analysis. Nearly 85% of breeding transgenic female mice developed mammary lobular adenocarcinomas by 12 months of age, while no tumors developed in non-transgenic littermates. Salivary gland tumors occurred in some animals, always in association with mammary tumors. Several MMTV-Fgf8b transgenic mice had lung metastases at necropsy. The second transgene (MMTV-Fgf8) uses the entire Fgf8 gene and potentially encodes all FGF8 isoforms. Fgf8 is expressed by this transgene in several tissues in addition to those described above, notably the ovaries. The two MMTV-Fgf8 founders developed mammary ductal adenocarcinomas at five and eight months of age, and both displayed ovarian stromal hyperplasia. The founders expressing either transgene did not successfully nurse their pups. These results demonstrate that production of FGF8b, and possibly other FGF8 isoforms, in the mammary and salivary glands contributes to oncogenesis, and that ovarian expression results in stromal hyperplasia.

Adenocarcinoma↗

PubMed1997

Overlapping expression and redundant activation of mesenchymal fibroblast growth factor (FGF) receptors by alternatively spliced FGF-8 ligands.

FGF-8 is a member of the family of fibroblast growth factors and is expressed during vertebrate embryo development. Eight potential FGF-8 isoforms are generated by alternative splicing in mice, several of which are expressed during embryogenesis in epithelial locations. The significance of the multiple isoforms is currently unknown. In this report, we investigate the expression patterns and the specificity of the FGF-8 isoforms for known fibroblast growth factor (FGF) receptors. RNAs for seven of the eight potential isoforms are present at multiple sites of embryonic Fgf8 expression. None of the FGF-8 isoforms exhibited activity when assayed with BaF3 cells expressing the "b" splice forms of FGF receptors 1-3, which are mostly expressed in epithelial tissues. Mesenchymally expressed "c" splice forms of FGF receptors 2 and 3 and FGF receptor 4 were activated by several FGF-8 isoforms. These findings are consistent with the hypothesis that the multiple FGF-8 isoforms are functionally redundant and function to signal in paracrine (epithelial to mesenchymal) contexts.

Alternative Splicing↗

PubMed1995

FGF-8 isoforms activate receptor splice forms that are expressed in mesenchymal regions of mouse development.

The Fgf8 gene is expressed in developing limb and craniofacial structures, regions known to be important for growth and patterning of the mouse embryo. Although Fgf8 is alternatively spliced to generate at least 7 secreted isoforms that differ only at their mature amino terminus, the biological significance of these multiple isoforms is not known. In this report, we demonstrate that multiple FGF-8 isoforms are present at sites of Fgf8 expression during mouse development. To address the possibility that the FGF-8 isoforms might interact with different fibroblast growth factor receptors, we prepared recombinant FGF-8 protein isoforms. We examined the ability of these proteins to activate alternatively spliced forms of fibroblast growth factor receptors 1-3, and fibroblast growth factor receptor 4. Recombinant FGF-8b and FGF-8c activate the 'c' splice form of FGFR3, and FGFR4, while FGF-8b also efficiently activates 'c' splice form of FGFR2. No activity could be detected for recombinant or cell expressed FGF-8a. Furthermore, none of the isoforms tested interact efficiently with 'b' splice forms of FGFR1-3, or the 'c' splice form of FGFR1. These results indicate that the FGF-8b and FGF-8c isoforms, produced by ectodermally derived epithelial cells, interact with mesenchymally expressed fibroblast growth factor receptors. FGF-8b and FGF-8c may therefore provide a mitogenic signal to the underlying mesenchyme during limb and craniofacial development.

Alternative Splicing↗

PubMed1995

FGF-8 isoforms differ in NIH3T3 cell transforming potential.

We previously identified Fgf-8 as a frequently activated gene in tumors from mouse mammary tumor virus-infected Wnt-1 transgenic mice, suggesting that Fgf-8 is a proto-oncogene. We further determined that multiple, secreted protein isoforms that differ at their mature amino termini are encoded by alternatively spliced mRNAs transcribed from the gene. We now present evidence that there are differences in the potency of NIH3T3 cell transformation displayed by three of the FGF (fibroblast growth factor)-8 isoforms. We find that stable transfection of a cDNA for the FGF-8b isoform leads to marked morphological transformation of NIH3T3 cells and rapid tumorigenicity of the transfected cells in nude mice. In contrast, transfection of a cDNA for the FGF-8a or FGF-8c isoform results in moderate morphological changes in the NIH3T3 cells, and the transfected cells are weakly tumorigenic in nude mice. All three transfections result in cells that express comparable amounts of Fgf-8 mRNA and that produce the FGF-8 protein isoforms. The morphological changes observed in NIH3T3 cells can be reproduced by the addition of recombinant FGF-8 protein isoforms to the culture medium. Therefore, these results indicate that there are differences in the potency of transformation of NIH3T3 cells by FGF-8 protein isoforms and suggest that these FGF-8 isoforms may have different in vivo functions.

3T3 Cells↗

PubMed1994

Fgf-8 expression in the post-gastrulation mouse suggests roles in the development of the face, limbs and central nervous system.

Fgf-8 is a member of the fibroblast growth factor (FGF) family that was initially identified as an androgen-inducible growth factor in a mammary carcinoma cell line. Alternative splicing of the primary Fgf-8 transcript results in three messenger RNAs which code for secreted FGF-8 protein isoforms that differ only in their mature amino termini. Fgf-8 RNA is present from day 10 through 12 of murine gestation when analyzed by northern blot analysis, suggesting that Fgf-8 normally functions during post-gastrulation development. To characterize the temporal, spatial and isoform-specific aspects of Fgf-8 expression during mouse development, we performed in situ hybridization and ribonuclease protection assays between the days 8 and 16 of gestation. Fgf-8 expression is first detected at day 9 of gestation in the surface ectoderm of the first branchial arches, the frontonasal process, the forebrain and the midbrain-hindbrain junction. At days 10-12 of gestation, Fgf-8 expression is detected in the surface ectoderm of the forelimb and hindlimb buds, in the nasal pits and nasopharynx, in the infundibulum and in the telencephalon, diencephalon and metencephalon. Fgf-8 expression continues in the developing hindlimbs through day 13 of gestation but is undetectable thereafter. Ribonuclease protection assays reveal that RNAs coding for all three FGF-8 isoforms are present at days 10-12 of gestation. These results reveal a unique temporal and spatial pattern of Fgf-8 expression in the developing mouse and suggest a role for this FGF in multiple regions of ectodermal differentiation in the post-gastrulation mouse embryo.

Animals↗