ADH1 AND ADH4 ALCOHOL RETINOL DEHYDROGENASES IN THE DEVELOPING ADRENAL BLASTEMA PROVIDE EVIDENCE FOR EMBRYONIC RETINOID ENDOCRINE FUNCTION/

Studies on retinoid signaling indicate that much of the regulation of this pathway may involve enzymes that synthesize the active ligand ret inoic acid. Alcohol dehydrogenases ADH1 (class I ADH) and ADH4 (class IV ADH) function as retinol dehydrogenases in the oxidation of retinol , a necessary step in the synthesis of retinoic acid from vitamin A. T hese enzymes as well as retinoic acid have previously been localized i n the adult adrenal gland, thus providing evidence that this organ is an endocrine source of retinoic acid. Here, we have examined the invol vement of ADH1 and ADH4 in embryonic adrenal function by using transge nic mouse technology and immunohistochemistry. Transgenic mice were ge nerated that contain various portions of the mouse ADH4 promoter and 5 '-flanking region fused to lacZ. Embryos harboring a construct contain ing 9.0 kb of 5'-flanking region displayed very high levels of lacZ ex pression in the developing adrenal blastemas at embryonic stage E11.5 during. the initial phase of mouse adrenal gland development, The pres ence of endogenous ADH4 protein in stage E11.5 adrenal blastemas was d emonstrated by immunohistochemistry, and this was the only site of ADH 4 immunodetection in stage E11.5 embryos, Endogenous ADH1 protein was also detected by immunohistochemistry in stage E11.5 adrenal blastemas , ADH1 and ADH4 proteins were detectable at later stages of adrenal de velopment, and both were localized to developing adrenal cortical cell s by stage E14.5. The presence of both ADH1 and ADH4 retinol dehydroge nases during the earliest stages of adrenal gland development, combine d with our earlier findings of high levels of retinoic acid in the emb ryonic adrenal gland, suggests that one of the earliest functions of A DH may be to provide an embryonic endocrine source of retinoic acid fo r growth and development, Dea Dyn. 1998;213:114-120. (C) 1998 Wiley-Li ss, Inc.