Elsevier

Neurotoxicology and Teratology

Volume 21, Issue 2, March–April 1999, Pages 141-146
Neurotoxicology and Teratology

Articles
Postnatal Effects of Retinoic Acid on Cerebellar Development

https://doi.org/10.1016/S0892-0362(98)00048-8Get rights and content

Abstract

Retinoic acid (RA) is a potent teratogen to which the early CNS is known to be highly sensitive. However, very little is known about the postnatal effects of RA. The cerebellum is a candidate for postnatal RA toxicity, as it develops late and exhibits temporal patterns of RA synthesis that are synchronized with developmental stages. Northern blotting shows that the cerebellum expresses receptors for RA, predominantly of the RXR group activated by 9-cis RA. To determine whether development can be disrupted by RA excess, newborn rats were injected with RA at a time when endogenous RA levels are normally low. Histological examinations at postnatal day 14 revealed loss of a subpopulation of proliferating granule cells, and adult cerebella showed clusters of ectopic granule cells located in the molecular layer. Thus, although the granule cells may normally be regulated by endogenous RA, they are sensitive to abnormally high RA concentrations.

Section snippets

Animals

Mice were raised in a B6/D2 outbred colony and embryos were staged following Theiler’s criteria (25), where the day of conception is defined as embryonic day 0. The first postnatal day was defined as postnatal day 0. Pregnant Sprague–Dawleys were obtained from Zivic-Miller Laboratories and from SLC; the labeling of developmental ages in rats was the same as in mice.

A total of 96 animals was used: 53 injected with RA that were compared to 33 dimethyl sulfoxide (DMSO)-injected controls and 10

RA Receptors

We used Northern blotting to determine which of the six RA receptors were present in the cerebellum. Of the RA receptor class that responds to both the all-trans and 9-cis isomers of RA, RARα, β, and γ, only RARβ was detectable in the cerebellum. The transcript size of 3.0 and 3.5 kb (Fig. 1A) was similar to the 3.3 and 3.5 kb transcripts described in a mouse embryonic cell line (28), although a larger, nonspecific band was also evident. RARβ expression increased during postnatal development

Discussion

Although vitamin A teratogenicity has been studied extensively in embryonic rodents over the last 40 years (4), little is known about the influence of RA on postnatal development. Postnatal developmental events sensitive to exogenous RA are those that normally respond to endogenous RA and that continue into postnatal life, such as lung development (5). Cerebellar development also continues postnatally, and we have shown that RA is likely to be involved in its regulation (30). Two tissues

Acknowledgements

We thank Dr. P. Dolle and Dr. P. Chambon for RA receptor plasmids. This work was supported by a grant from the Japanese Ministry of Education, Science, Sports and Culture to M. Y., grant AA09493 to D. U., grant EY01938 to U. D. and grants HD05515 and HD01179 to P. McC.

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