Forebrain induction, retinoic acid, and vulnerability to schizophrenia: Insights from molecular and generic analysis in developing mice

Schizophrenia is thought to be a disease of early development that ultimate ly affects forebrain neurons and circuits. There may be a relationship betw een disrupted forebrain development; malformations of the limb, face, and h eart, and signaling via the steroid-like hormone retinoic acid (RA) in some schizophrenic patients. The limbs, face, heart, and forebrain all develop from sites where neural crest-derived, RA-producing mesenchyme contributes to induction and differentiation of adjacent epithelia. Induction between n eural crest-derived, RA-producing mesenchyme, the anterior neural tube, and the anterior surface epithelium of the embryo guides regional differentiat ion and pathway formation during forebrain development. Furthermore, there are at least two mouse mutations-in the Pax-6 and Gli-3 genes-that cause pe ripheral malformations and specifically disrupt neural crest mediated, RA-d ependent induction and differentiation in the forebrain. These observations suggest that induction might provide a common target for genes that alter morphogenesis of peripheral structures, disrupt RA-signaling, and compromis e forebrain development In the forebrain, some of these disruptions might i nfluence the numbers or cellular properties of neurons and circuits. Such c hanges might be reflected in the aberrant forebrain function that character izes schizophrenia. (C) 1999 Society of Biological Psychiatry.