ADH4-LACZ TRANSGENIC MOUSE REVEALS ALCOHOL-DEHYDROGENASE LOCALIZATIONIN EMBRYONIC MIDBRAIN HINDBRAIN, OTIC VESICLES, AND MESENCEPHALIC, TRIGEMINAL, FACIAL, AND OLFACTORY NEURAL CREST/

Pursuit of endogenous functions for various members of the alcohol deh ydrogenase (ADH) enzyme family has led to exploration of gene expressi on patterns. Herein, we have used transgenic mice to examine the mouse gene encoding class IV ADH (ADH4), an enzyme that is weakly effective as an ethanol dehydrogenase, but highly effective as a retinol dehydr ogenase in vitro. ADH4 promoter and upstream regulatory sequences were fused to lacZ and stably introduced into mice so that embryonic expre ssion of ADH4 could be easily monitored by examination of P-galactosid ase activity in situ. Several independent founder mice carrying ADH4-l acZ transgenes with either 2.7 or 9.0 kb of upstream regulatory sequen ces produced embryos in which expression was highly localized in the b rain and craniofacial region at stages E8.5 to 9.5 during neurulation. Expression in the brain was limited to the ventral midbrain and its b oundary with the hindbrain. At stage E8.5, ADH4-lacZ expression was no ticed in several dispersed regions throughout the head, and by stage E 9.5 it was evident that these regions corresponded to the otic vesicle s and migrating neural crest cells, particularly the mesencephalic, tr igeminal, facial, and olfactory neural crest. ADH4-lacZ expression in the trigeminal neural crest appeared as long fibers emanating from the midbrain/hindbrain boundary and extending to the first branchial arch following the tract of the trigeminal nerve. These findings support t he hypothesis that ADH4 may normally function in retinoic acid synthes is needed for brain and neural crest development and that it participa tes in the mechanism of ethanol-induced brain and craniofacial birth d efects.