The Meninges Is a Source of Retinoic Acid for the Late-Developing Hindbrain

Jinghua Zhang,Lanhua Ma,Deborah Smith,Peter Mccaffery,Miyuki Yamamoto

doi:10.1523/jneurosci.23-20-07610.2003

Abstract

One general function for retinoic acid (RA) is pattern organization in the CNS. This regulatory factor has an essential role in spinal cord motor neuron and early posterior hindbrain development. In the anterior CNS, however, there is only a limited number of foci of RA synthesis, and less attention has been placed on regions such as the anterior hindbrain where RA synthesizing enzymes are absent. This study shows that a rich source of RA lies around the hindbrain from the RA synthetic enzyme retinaldehyde dehydrogenase-2 (RALDH2) present in the surrounding meninges and mesenchyme by embryonic day 13. RALDH2 is not distributed uniformly throughout the meninges but is restricted to territories over the developing hindbrain, suggesting that RA signaling may be localized to those regions. Further regulation of RA signaling is provided by the presence of a RA sink in the form of the CYP26B1 RA catabolic enzyme expressed in deeper regions of the brain. As a guide to the neural anatomy of hindbrain RA signaling, we used a mouse transgenic for a lacZ reporter gene driven by a RA response element (RAREhsplacZ) to identify regions of RA signaling. This reporter mouse provides evidence that RA signaling in the hindbrain after embryonic day 13 occurs in the regions of the cerebellum and precerebellar system adjacent to sources of RA, including the inferior olive and the pontine nuclei.

Highlights

Vitamin A is required for normal embryonic development
The components of the precerebellar system all project to the cerebellum and consist of the pontine and reticulotegmental nuclei in the pons, generated from the anterior precerebellar neuroepithelium and the inferior olive, external cuneate, and lateral reticular nuclei, which arise from the posterior precerebellar neuroepithelium (Altman and Bayer, 1987)
It is apparent that cellular RA binding protein-I (CRABPI) is present in all the precerebellar neurons that migrate under the meninges. These results suggest that retinoic acid (RA) regulated transcription occurs in the developing pontine nuclei as the pontine neuronal progenitors express CRABPI as they migrate from the rhombic lip under the retinaldehyde dehydrogenase-2 (RALDH2) rich meninges (Fig. 4)

Summary

Introduction

Vitamin A (retinol) is required for normal embryonic development. Its metabolic product, retinoic acid (RA), mediates the majority of its actions by binding to specific nuclear receptors and regulating gene transcription. The hindbrain itself does not express high amounts of RA-synthesizing enzymes; a source of RA for hindbrain patterning lies in the adjacent spinal cord and surrounding mesenchyme that express high levels of retinaldehyde dehydrogenase-2 (RALDH2) (Guthrie, 1996; Niederreither et al, 1997; Swindell et al, 1999) This posterior source of RA would correspond with a posterior function for RA in hindbrain development, which is consistent with the phenotype of the null mutants of RALDH2 (Niederreither et al, 2000) or RA receptors ␣ and ␤ (Dupe et al, 1999), each of which exhibits disorganization

Methods

Results

Conclusion