Retinoic Acid Synthesis in Mouse Embryos during Gastrulation and Craniofacial Development Linked to Class IV Alcohol Dehydrogenase Gene Expression

Abstract

Endogenous retinoic acid (RA) has been observed in vertebrate embryos as early as gastrulation, but the mechanism controlling spatiotemporal synthesis of this important regulatory molecule remains unknown. Some members of the alcohol dehydrogenase (ADH) family catalyze retinol oxidation, the rate-limiting step in RA synthesis. Here we have examined mouse embryos for the presence of endogenous RA and expression of ADH genes. RA was not detected in egg cylinder stage embryos but was detected in late primitive streak stage embryos. Detection of class IV ADH mRNA, but not class I or class III, coincided with the onset of RA synthesis, being absent in egg cylinder embryos but present in the posterior mesoderm of late primitive streak embryos. During neurulation, RA and class IV ADH mRNA were colocalized in the craniofacial region, trunk, and forelimb bud. Class IV ADH mRNA was detected in cranial neural crest cells and craniofacial mesenchyme as well as trunk and forelimb bud mesenchyme. The spatiotemporal expression pattern and enzymatic properties of class IV ADH are thus consistent with a crucial function in RA synthesis during embryogenesis. In addition, the finding of endogenous RA and class IV ADH mRNA in the craniofacial region has implications for the mechanism of fetal alcohol syndrome.

Ascidian and Amphioxus Adh Genes Correlate Functional and Molecular Features of the ADH Family Expansion During Vertebrate Evolution

“…Some of the newly generated forms deserve further consideration. ADH4 has been assumed to be crucial in vertebrates for retinoic acid synthesis via retinol oxidation (Duester 1996). Retinoic acid is thought to be involved in the anterior/posterior axis formation in both ascidian and amphioxus and, also, in vertebrates (reviewed by Shimeld 1996).…”

“…Whereas a ubiquitous Adh3 expression has been shown in mouse and human (Giri et al 1989;Ang at al. 1996;Estonius et al 1996), a specific expression, restricted to the midgut region, has been shown in amphioxus by in situ hybridization (Cañestro et al 2000).…”

Retinal dehydrogenase gene expression in stomach and small intestine of rats during postnatal development and in vitamin A deficiency

“…In vitamin A de¢ciency, the forestomach shows hyperkeratosis and the number of goblet cells of the small intestine severely declines [13]. Because RA is involved in the epithelial cell di¡erentia-tion of the stomach and small intestine, and also because the endogenous RA levels in embryonic tissues are controlled by developmentally regulated mechanisms that are likely to include modulation of expression and/or activity of enzymes catalyzing RA synthesis [14,15], it was of interest to examine the developmental pattern of RALDH gene expression in these epithelial tissues. Further, we also studied the e¡ects of vitamin A status on RALDH gene expression in these tissues.…”

Evidence for the Expression of Alcohol Dehydrogenase Class I Gene in Rat Uterus and Its Up-regulation by Progesterone

“…Crystal structures of ADH class I and class IV revealed a conserved active site that can accommodate long chain alcohols such as retinol [18][19][20]. ADH class I is expressed at high levels in many retinoid target tissues of embryos [15,21] and in adult epithelia, such as intestine, kidney, adrenal gland, testis, epididymis, uterus and ovary [15,[22][23][24][25]. Retinoid signaling is thought to function in an autocrine or paracrine fashion via the local production of RA at the site of action.…”