Disease relevance of Aldh1a3

• Raldh3 knockout notably causes choanal atresia (CA), which is responsible for respiratory distress and death of Raldh3-null mutants at birth [1].
• Mycoplasma pulmonis V-1 surface protein variation: occurrence in vivo and association with lung lesions [2].

High impact information on Aldh1a3

• We demonstrate that Raldh3 knockout in mouse suppresses RA synthesis and causes malformations restricted to ocular and nasal regions, which are similar to those observed in vitamin A-deficient fetuses and/or in retinoid receptor mutants [1].
• However, reporter transgene activity was selectively detected in Raldh2(-/-) embryos within the mesonephric area that expresses RALDH3 and in medial-ventral cells of the spinal cord and posterior hindbrain, up to the level of the fifth rhombomere [3].
• Although these patterns correlated with the presence of Raldh1 andor Raldh3 transcripts in eye, nasal, and inner ear epithelia, no such correlation was found within forebrain neuroepithelium [3].
• These data suggest the existence of additional RA-generating activities in the differentiating forebrain, hindbrain, and spinal cord, which, along with RALDH1 and RALDH3, may account for the development of Raldh2(-/-) mutants once these have been rescued for early lethality [3].
• RA signaling in the optic cup, detected by using a RARE-lacZ transgene, is not significantly altered in Raldh1(-/-) embryos at embryonic day 10.5, possibly due to normal expression of Aldh1a3 (Raldh3) in dorsal retinal pigment epithelium and ventral neural retina [4].

Biological context of Aldh1a3

• Three retinaldehyde dehydrogenases (RALDH1, RALDH2 and RALDH3), which catalyze the oxidation of retinaldehyde into retinoic acid, have been shown to be differentially expressed during early embryogenesis [5].
• Using genetic approaches in the mouse, we show that the primary target tissue of retinoic acid (RA) action during eye morphogenesis is not the retina nor the corneal ectoderm, which both express RA-synthesizing retinaldehyde dehydrogenases (RALDH1 and RALDH3), but the neural crest cell-derived periocular mesenchyme (POM), which is devoid of RALDH [6].
• Here we describe the distribution of three synthesizing enzymes, retinaldehyde dehydrogenases 1, 2 and 3 (RALDH1, RALDH2 and RALDH3) and two catabolizing enzymes (CYP26A1 and CYP26B1) in the mouse inner ear at embryonic day 18.5 when active cell differentiation is underway [7].

Anatomical context of Aldh1a3

• Raldh-3 was preferentially expressed first in the surface ectoderm overlying the ventral portion of the prospective eye region and then in the ventral retina, earlier than Raldh-1 in chick and mouse embryos [8].
• Within the optic vesicle, RALDH3 is expressed in the ventral retina and the dorsal pigment epithelium [9].
• Raldh3 expression is specific to the differentiating intestinal lamina propria [5].
• In the telencephalon, RALDH3 is expressed at high levels in the lateral part of the ganglionic eminence [9].
• At later stages, Raldh1 expressed in dorsal neural retina and Raldh3 expressed in ventral neural retina (plus weaker expression of each in lens/corneal ectoderm) generates RA that travels to surrounding mesenchyme, where it is needed to limit the anterior invasion of perioptic mesenchyme during the formation of corneal mesenchyme and eyelids [10].

Associations of Aldh1a3 with chemical compounds

• Since this molecule showed enzymatic activity to produce RA from retinaldehyde, we designated it retinaldehyde dehydrogenase 3 (RALDH-3) [8].
• These results suggested that Raldh-3 is the key enzyme in the formation of an RA gradient along the dorso-ventral axis during the early eye development, and also in the development of the olfactory system [8].
• Hair cycle-specific immunolocalization of retinoic acid synthesizing enzymes Aldh1a2 and Aldh1a3 indicate complex regulation [11].
• We have isolated the chick and mouse homologs of human aldehyde dehydrogenase 6 (ALDH6) that encode a third cytosolic retinaldehyde-specific aldehyde dehydrogenase [12].
• Recombinant chick ALDH6 has a K(0.5) = 0.26 microm, V(max) = 48.4 nmol/min/mg and exhibits strong positive cooperativity (H = 1.9) toward all-trans-retinaldehyde; mouse ALDH6 has similar kinetic parameters [12].

Other interactions of Aldh1a3

• In addition, we found that Pax6 mutants are devoid of Raldh-3 expression [8].
• In mouse embryos, RALDH3 expression is first noticed in the ventral optic eminence at E8.75, then in the optic vesicle/cup, otic vesicle, and olfactory placode/pit from E9.5 to E11 [13].
• Immunohistochemistry confirmed RALDH4 expression in hepatocytes and showed that hepatocytes also express RALDH1, RALDH2, and RALDH3 [14].

Analytical, diagnostic and therapeutic context of Aldh1a3

• Immunohistochemistry was performed on adult C57BL/6J mouse skin sections with antibodies against Aldh1a2 and Aldh1a3 [11].
• RALDH3 (retinal dehydrogenase 3) was characterized by kinetic and binding studies, protein engineering, homology modelling, ligand docking and electrostatic-potential calculations [15].
• Inhibition of RALDH3 by tri-iodothyronine binding in competition with NAD+, predicted by the modelling, was established kinetically and by immunoprecipitation [15].

References