This proposal is in response to RFA 91-HD-09. Its purpose is to explore the relationships between retinoic acid receptors and neural tube defects using the curly-tailed(ct/ct) mouse model. Our laboratory has been studying the steroid-like retinoic acid receptors(RARs) and retinoid receptors(RXRs) during development and differentiation. We have constructed dominant-negative expression vectors for regions of the receptors and have shown we can interfere with receptor function in cells in culture. To identify where activated receptors are in the developing embryo, we have used transgenic technology to produce """"""""indicator mice"""""""" which have retinoic acid receptor responsive sequences coupled to the bacterial beta-galactosidase gene. We plan to use these technologies to investigate the relationships between retinoids and phenotypic expression of neural tube defects in ct/ct homozygotes. 1)Introduce our indicator transgene for activated RARs into the ct/ct background so that observed changes in the beta-galactosidase staining patterns might implicate activated RARs in the phenotype. 2)Since the ct/ct phenotype is not completely penetrant, we will make aggregation chimeras between morula from our homozygous transgenic indicator mice and morula from ct/ct embryos to see if extent of penetrance of the ct/ct phenotype might depend upon the presence and availability of retinoids in the ct/ct embryo. 3)We will examine the DNA of ct/+ and ct/ct DNA for any obvious abnormalities in the genomic structure of RAR-alpha, RAR-beta, RAR-gamma, RXR-alpha, RXR-beta and possibly RXR-gamma. 4)Produce additional transgenic indicator mice with specificities for either other RARs or RXRs. 5)To use expression vectors for receptors to either attempt to repair possible receptor defects in ct/ct mice or to reproduce the ct/ct phenotype in normal mice.
| Colbert, M C; Rubin, W W; Linney, E et al. (1995) Retinoid signaling and the generation of regional and cellular diversity in the embryonic mouse spinal cord. Dev Dyn 204:1-12 |
| Underhill, T M; Cash, D E; Linney, E (1994) Constitutively active retinoid receptors exhibit interfamily and intrafamily promoter specificity. Mol Endocrinol 8:274-85 |
| Smith, B R; Johnson, G A; Groman, E V et al. (1994) Magnetic resonance microscopy of mouse embryos. Proc Natl Acad Sci U S A 91:3530-3 |
| Colbert, M C; Linney, E; LaMantia, A S (1993) Local sources of retinoic acid coincide with retinoid-mediated transgene activity during embryonic development. Proc Natl Acad Sci U S A 90:6572-6 |
