Expression of a retinoic acid response element-hsplacZ transgene defines specific domains of transcriptional activity during mouse embryogenesis.

Abstract

Treatment with retinoic acid (RA) is known to produce complex teratogenic effects in vertebrates, and its presence in the developing embryo as an endogenous substance has led to the suggestion that RA might be a natural morphogenetic agent. Although our understanding of the molecular mechanism of RA action has improved considerably with the identification of nuclear receptors for RA (RARs) and RA-responsive genes, the exact relationship between the proposed morphogenetic activity of RA and its teratogenic effects remains to be characterized. Here, we show that a RA response element (RARE) present in the RARI3 gene can direct specific spatial and temporal expression of an hsplacZ transgene during mouse embryogenesis. In the early embryo, the transgene is expressed in a specific anterior-posterior domain that is completely obliterated by treatment of pregnant mice with teratogenic doses of RA. The expression of the transgene becomes more restricted as organogenesis progresses and mimics closely the reported expression of the RARI$ gene. These results suggest that, in vivo, some of the morphogenetic effects of RA could be mediated through localized transcriptional activity controlled by the various RARs. The specific pattern of expression of the RAREhsplacZ transgene does not correlate with the proposed sites of action of RA as defined by its teratogenic effects but does support a role for RA in early anterior-posterior patterning along the body axis.

Endogenous distribution of retinoids during normal development and teratogenesis in the mouse embryo

“…The observation made in this study that the spinal cord is particularly enriched with tRA is supported by the results of more indirect methods of detection, for instance, mice injected with the RAREhspZacZ or RAREtkpZacZ transgenes. In this situation, activation of the transgene occurs from the caudal hindbrain, then all along the length of the spinal cord, but no activation occurs in the midbrain or forebrain (Rossant et al, 1991;Balkan et al, 1992). Similar results were obtained by culturing mouse embryonic neural tissue with RAREZucZ transfected F9 cells (Wagner et al, 1992;Colbert et al, 1993).…”

Retinoic acid down‐regulates Tbx1 expression in vivo and in vitro

“…The explanation for this discrepancy between the mouse and avian data may be that, in the VAD embryos, there is no dietary vitamin A. Thus, all the embryonic RA production pathways, including those mediated by retinol dehydrogenases, e.g., adh1 and adh4 (Rossant et al, 1991;Vonesch et al, 1994;Haselbeck and Duester, 1998), and retinaldehyde dehydrogenases such as Raldh1, 2 and 3 (Blentic et al, 2003;Fan et al, 2003) are blocked. In the hypomorphic raldh2 mouse mutants, only one RA-producing enzymatic pathway is partially blocked, perhaps resulting in a less severe effect upon Tbx1 expression.…”

Retinoid signaling and the generation of regional and cellular diversity in the embryonic mouse spinal cord

“…The developing spinal cord becomes divided into four functionally distinct regions: the cervical, thoracic, lumbar, and sacral domains. By mid-gestation the expression of several RA-responsive genes is apparently confined to the cervical and lumbar regions Rossant et al, 1991;Balkan et al, 1992). We have suggested previously that this pattern reflects, in part, the local availability of the inductive signaling molecule RA ; see also McCaffery and Drager, 1994).…”