Pathogenesis in Transgenic Mice Expressing Bovine Cellular Retinoic Acid‐Binding Protein

Abstract

Transgenic mice with ectopic expression of bovine CRABP under the control of the human metallotheionein IIA promoter have shown a variety of pathological consequences. Expression of the transgene has been detected in most of the tissues examined, including heart, lung, liver, spleen, kidney, intestine, testis, and ovary, except pancreas. Two independent lines have been able to produce normal non‐transgenic F1 animals of both sexes but only female transgenic progenies. All of these F1 female transgenic animals derived from both lines are sterile, and the ovaries from these animals appear to be significantly smaller as compared to their non‐transgenic littermates. Histopathological examinations have shown no maturing follicles in these transgenic ovaries in which abnormal cells have been observed. Another independent line has generated transgenic F1 animals which have been growing retardly. These animals all have small spleen and liver and have become very sick at the age of 4 to 5 weeks. Histopathological examinations on these transgenic progenies have shown hepatocytes to be reduced in the cytoplasmic portion in which glycogen is highly depleted. The spleen is poorly developed as no well organized germinal centers can be observed in the spleen sections of these transgenic animals.

Demethylation in the 5′‐flanking region of mouse cellular retinoic acid binding protein‐I gene is associated with its high level of expression in mouse embryos and facilitates its induction by retinoic acid in P19 embryonal carcinoma cells

“…In transgenic mice ectopically expressing this protein, a variety of pathological consequences have been observed, which mimic the outcome of hypovitaminosis A in animals (Wei et al, 1992). Thus, it is possible that fine-tuning regulatory mechanisms for CRABP-I gene are needed for its expression regarding the level, timing, and inducibility.…”

“…Cellular retinoic acid binding protein-I (CRABP-I) is one of the cytosolic binding proteins (Chytil and Ong, 1984) for retinoic acid (RA). Based on studies of its expression patterns in embryos (Dolle et al, 1990;Wei et al, 1991) and the phenotypes associated with an alteration in its level of expression (Boylan and Gudas, 1991;Wei et al, 1992), it is proposed that this protein may be involved in modulating intracellular RA concentration through a trapping mechanism. Based upon data showing its ubiquitous expression in animals (Kato et al, 1985) and the feature of its promoter sequence (Wei et al, 1990), this gene has been characterized as a housekeeping gene.…”

Chromatin remodeling and epigenetic regulation of the CrabpI gene in adipocyte differentiation

“…, such cells are more resistant to RA induction of gene expression [10–12]. Consistent with the notion that binding to CRABPI reduces the cellular availability of RA for general growth, studies in transgenic mice showed that globally over-expressing CRABPI produced specific pathologies in growth and reproduction, as well as abnormalities of the liver and spleen [27, 28]. In contrast, mutating CRABPI (specifically, with regard to its RA-binding affinity) eliminated its ability to desensitize the response of cells to RA [12].…”

Characterization of a Negative Response DNA Element in the Upstream Region of the Cellular Retinoic Acid-binding Protein-I Gene of the Mouse

“…Although mice deficient in this gene seemed normal phenotypically, several studies showed that overexpression of this gene altered cellular differentiation (20) or the expression of certain developmental genes (21). Thus, the absence of this gene was not devastating to animal survival, but overexpression of this protein affected cell differentiation in both transgenic mice and cell cultures.…”

“…However, it was demonstrated in transgenic mice (20) and embryonal carcinoma cells (21) that elevated CRABP-I expression was associated with abnormal cellular differentiation and RA-responsive gene expression. It was also shown in embryonic palate cells that the expression of RAR ␤ , transforming growth factor ␤3, and tenascin was altered as a result of introducing anti-crabp-I oligonucleotides into the cultures (22).…”