by the presence of retinal dehydrogenases exclusively in chordates. Retinoic acid signaling appears to control developmental processes like neurogenesis, cardiogenesis, forelimb bud development, foregut development, and eye development. Retinoic acid signaling is also important for maintaining adult neuronal and epithelium cell type. Retinoic acid is generated in organisms by first oxidizing retinol (Vitamin A) to retinal with an alcohol dehydrogenase. Then, a retinal dehydrogenase oxidizes retinal to retinoic acid. The production of retinoic acid from vitamin A must be tightly controlled as high levels of retinoic acid and vitamin A can lead to toxic effects, while vitamin A deficiency leads to its own issues in development. This provides a rationale for many of the transcriptional regulatory strategies discussed earlier. In humans, mutations in a gene coding for a certain retinal dehydrogenase (RDH12) can also lead to Leber's congenital amaurosis, a retinal dystrophy responsible for many cases of congenital blindness. Isoforms Different isoforms of retinal dehydrogenase exist and play a key role in development, as the types are differentially expressed inside a developing embryo. The enzyme retinal dehydrogenase type-2 (RALDH2) catalyzes much of the retinoic acid formation during development, but not all. RALDH2 is crucial for development midgestation and helps drive neural, heart, lung, and forelimb development; it is also responsible for all retinoic acid development during certain periods of midgestation. Later in development, retinal dehydrogenase type-1 (RALDH1) begins activity in the dorsal pit of the retina and retinal dehydrogenase type-3 (RALDH3) becomes active in the olfactory pit, ventral retina, and urinary tract. Raldh2 gene knockouts are fatal in mice during development since the brain cannot develop normally. Raldh3 gene knockout is fatal at birth in mice since nasal passages are not properly developed and instead are blocked. Raldh1 knockouts are not fatal and, interestingly, have been shown to be protective against diet-induced obesity in mice in a retinoid-independent manner. References EC 1.2.1 NADH-dependent enzymes Metal enzymes