A necessary poison: a mechanism by which retinoic acid can be both essential and harmful for the developing hindbrain

Abstract

Retinoic acid (RA) is known to many as a Sigma reagent to be purchased to induce differentiation of a favorite progenitor cell line, whether it be the hemopoietic cell line HL60 or a neural stem cell. The developing embryo uses RA in the same way, to regulate cell differentiation and patterning. The amount of this potent transcriptional activator is determined through regulation of the enzymes that either synthesize RA from vitamin A or inactivate RA. This dependence on precisely regulated amounts of RA renders the embryo acutely sensitive to RA as a teratogen. Exposure of the human embryo can occur because RA is used to treat chronic cystic acne. The abnormalities in the CNS are many but the hindbrain is particularly sensitive. Our studies show that RA exposure of the mouse at a specific embryonic stage alters morphological structures that derive from the wall of the IV ventricle and form the cerebellar system of the hindbrain (i.e. the cerebellum, the inferior olivary nucleus and the pontine nucleus). The loss of the cerebellar vermis in the mouse requires chronic exposure of the embryo to RA whereas abnormalities in the pontine nuclei and inferior olive results from exposure at a critical period of embryonic day 9.5 and 10.5. The abnormalities in the pontine nuclei are due to a failure in their usual neurophilic migration. The compact stream of cells, which leads from the anterior rhombic lip to the ventral pons, is instead scattered widely over the anterior medulla. Given that the RA exposure occurs after the resolution of rhombomere identity this suggests that teratogenic RA interferes with a regulatory event which overlays this original pattern.