The Vitamin A Paradox: Too Much or Too Little Impacts Development and Disease

Vitamin A is essential for proper human embryonic development particularly with respect to brain, craniofacial, limb, and organ, patterning and morphogenesis. Later, in adulthood, vitamin A plays important roles in fertility, immune function, maintenance of vision, and skeletal homeostasis. Surprisingly, deficiency or excess of vitamin A and its metabolic derivative, retinoic acid, can elicit similar effects. Therefore, strict feedback and other mechanisms must exist to regulate levels within a narrow physiological range. We discovered retinol dehydrogenase 10 (Rdh10) as a novel critical regulator of vitamin A metabolism and retinoic acid (RA) synthesis during embryogenesis. Rdh10 oxidizes all trans retinol (vitamin A) to retinal, which is then oxidized by retinaldehyde dehydogenases to retinoic acid. Rdh10 loss‐of‐function mouse embryos exhibit craniofacial anomalies such as choanal atresia, facial clefts, and abnormal branchiomeric muscle development, cardiac malformations including choanal atresia, and gastrointestinal defects such as Hirschsprung disease. Underpinning each phenotype were defects in the development of neural crest cells, a migratory progenitor cell population essential for normal craniofacial and organ morphogenesis. We determined that Rdh10 and retinoic acid signaling are precisely required between embryonic day (E) 7.5‐9.5 in both an intrinsic/autocrine and extrinsic/paracrine manner for proper neural crest cell development. Thus, Rdh10 forms a key nodal point in the regulation of vitamin A metabolism and retinoic acid synthesis and is essential for regulating basic developmental and homeostasis signaling pathways. Furthermore, Rdh10 and vitamin A signaling are both genetic and non‐genetic risk factors in the etiology and pathogenesis of congenital birth defects.