Affinage

RDH10

Retinol dehydrogenase 10 · UniProt Q8IZV5

Length
341 aa
Mass
38.1 kDa
Annotated
2026-04-28
19 papers in source corpus 14 papers cited in narrative 14 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RDH10 is a membrane-associated, NAD⁺-dependent short-chain dehydrogenase/reductase that catalyzes the rate-limiting first oxidative step in retinoic acid (RA) biosynthesis—the conversion of all-trans-retinol to all-trans-retinal—with the lowest known Km (~0.035 µM) among NAD⁺-dependent retinoid oxidoreductases (PMID:18502750). The enzyme resides at mitochondria-associated membranes and lipid droplets, where its membrane compartmentalization shields it from inhibition by cytosolic CRBP1; N-terminal and C-terminal hydrophobic domains govern its dual targeting (PMID:23155051, PMID:21782811). In the visual cycle, RDH10 also oxidizes 11-cis-retinol to 11-cis-retinal and physically interacts with RPE65 and CRALBP to reconstitute chromophore production (PMID:19458327). Spatiotemporally regulated RDH10 activity in mesenchymal tissues is essential for local RA production that controls craniofacial morphogenesis, limb interdigital apoptosis, choanae formation, salivary gland initiation, fetal mouth movement, enteric nervous system development, and postnatal metabolic homeostasis through downstream RAR-mediated transcription (PMID:17473173, PMID:21360789, PMID:28169399, PMID:29986869, PMID:31300413, PMID:29321172).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2004 High

    Establishing that RDH10 possesses retinol dehydrogenase activity and is membrane-associated answered the basic question of its enzymatic identity and subcellular context, initially placing it as a microsomal NADP⁺-dependent enzyme in retinal Müller cells.

    Evidence Western blot, immunohistochemistry, HPLC-based enzymatic assay on microsomal fractions of bovine retinal cells

    PMID:15505029

    Open questions at the time
    • Cofactor preference was later revised
    • Activity was measured only in retinal cells, not embryonic tissues
    • No in vivo loss-of-function data
  2. 2007 High

    Forward genetic identification of the trex mouse mutation in Rdh10 established it as the principal retinol dehydrogenase for embryonic RA synthesis, linking its catalytic activity to craniofacial, limb, and organ development in vivo.

    Evidence ENU mutagenesis screen in mice, enzymatic assays, mutant embryo phenotyping

    PMID:17473173

    Open questions at the time
    • Tissue-specific requirements were undefined
    • Whether other RDHs compensate partially was unclear
    • Downstream transcriptional targets not identified
  3. 2008 High

    Rigorous kinetic characterization corrected the cofactor specificity to NAD⁺ (not NADP⁺), revealed an exceptionally low Km for retinol, and demonstrated through siRNA knockdown that RDH10 is required for RA production in human cells, establishing its biochemical parameters.

    Evidence Kinetic enzyme assays with purified protein, siRNA knockdown in human cells, retinoid quantification

    PMID:18502750

    Open questions at the time
    • Structural basis for NAD⁺ selectivity unknown
    • Regulation of enzyme turnover not addressed
  4. 2009 High

    Demonstrating that RDH10 oxidizes 11-cis-retinol, physically interacts with RPE65 and CRALBP, and reconstitutes chromophore production when co-expressed with visual cycle components placed RDH10 within the retinal visual cycle.

    Evidence Co-immunoprecipitation, reconstitution assay in HEK-293A cells co-expressing RPE65/LRAT/CRALBP, HPLC retinoid profiling

    PMID:19458327

    Open questions at the time
    • In vivo contribution to visual cycle chromophore regeneration not tested
    • Structural basis of RPE65/CRALBP interaction not resolved
    • Relative contribution versus RDH5 or RDH11 in RPE unclear
  5. 2011 High

    Demonstrating that RDH10 operates in a membrane-bound compartment insulated from cytosolic CRBP1 inhibition, and that cytosolic RDH enzymes play only minor roles, resolved why membrane localization is functionally critical for embryonic RA synthesis.

    Evidence Rdh10(trex) mutant embryos, dietary retinaldehyde rescue, subcellular fractionation, RDH activity assays

    PMID:21782811

    Open questions at the time
    • Identity of the specific membrane compartment was not yet defined
    • How retinol accesses the membrane-bound enzyme from holo-RBP delivery was unresolved
  6. 2011 High

    Genetic analysis showed RDH10 is required for interdigital RA signaling and tissue regression but dispensable for limb patterning (Shh/Meis2), demonstrating tissue-specific selectivity of its developmental requirement.

    Evidence Rdh10(trex/trex) mutant limb analysis with RARE-lacZ reporter, RA rescue, skeletal staining

    PMID:21360789

    Open questions at the time
    • Direct RA targets mediating interdigital apoptosis not identified
    • Whether other RA sources supply the proximal limb was unresolved
  7. 2012 High

    Defining RDH10's dual localization to mitochondria/MAM and lipid droplets, governed by distinct N-terminal and C-terminal hydrophobic domains, resolved the membrane identity question and explained compartmentalized retinoid metabolism.

    Evidence Live-cell imaging, subcellular fractionation, domain deletion constructs, colocalization studies

    PMID:23155051

    Open questions at the time
    • How lipid droplet targeting affects catalytic output in vivo was not tested
    • No crystal structure to map targeting domains
  8. 2013 Medium

    Placing RDH10 in a PPARγ-regulated linear RA biosynthesis pathway in dendritic cells (upstream of RALDH2 and CRABP2) extended its functional role beyond embryogenesis into immune cell biology.

    Evidence siRNA knockdown in human monocyte-derived dendritic cells, PPARγ agonist treatment, ATRA quantification

    PMID:23833249

    Open questions at the time
    • Single lab finding in one immune cell type
    • In vivo immune phenotype of Rdh10 loss in DCs not examined
    • Whether PPARγ regulation of RDH10 is conserved across tissues is unknown
  9. 2017 High

    Tissue-specific conditional knockout revealed that RDH10 in non-neural crest cells is required before E10.5 for choanae formation, acting through regulation of Fgf8 expression and control of nasal epithelial proliferation and survival.

    Evidence Conditional Rdh10 mutant mice, Fgf8 in situ hybridization, cell proliferation and apoptosis assays

    PMID:28169399

    Open questions at the time
    • Whether Fgf8 is a direct or indirect RA target was not determined
    • Specific RAR isoform involved was not tested
  10. 2018 High

    Heterozygous Rdh10 mice display reduced tissue RA, increased adiposity, and metabolic defects rescued by RA supplementation, establishing that RDH10-dependent RA synthesis is haploinsufficient for postnatal metabolic homeostasis.

    Evidence Rdh10 heterozygote and knockout mouse models, LC-MS RA quantification, adipogenesis assays, pharmacological rescue

    PMID:29321172

    Open questions at the time
    • Tissue-specific metabolic requirements not dissected with conditional models
    • Downstream RAR target genes in adipose tissue not identified
  11. 2018 High

    RDH10-derived RA acts specifically through RARα to initiate submandibular salivary gland formation, with Rdh10 and Aldh1a2 co-expressed in the initiating mesenchyme, demonstrating RAR isoform specificity downstream of RDH10.

    Evidence Rdh10 conditional loss-of-function, ex vivo SMG initiation assay, RAR isoform-specific agonists/antagonists

    PMID:29986869

    Open questions at the time
    • Direct RA target genes in salivary gland mesenchyme not identified
    • Whether other RDHs partially compensate in this tissue is unknown
  12. 2019 High

    Revealing that Rdh10 loss causes mispatterned pharyngeal nerves and skeletal elements that physically block fetal mouth movement, leading to cleft palate, established a novel biomechanical mechanism downstream of RA signaling.

    Evidence Stage-specific Rdh10 inactivation, in utero ultrasound, X-ray microtomography, ex vivo culture

    PMID:31300413

    Open questions at the time
    • Which RA target genes control pharyngeal nerve patterning is unknown
    • Whether the biomechanical mechanism accounts for all RA-deficiency cleft palate cases is untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the atomic structure of RDH10, the full repertoire of direct RA-responsive target genes mediating its diverse developmental functions, the relative contribution of RDH10 versus other RDHs in adult tissues, and whether RDH10 mutations cause human Mendelian disease.
  • No crystal or cryo-EM structure available
  • Systematic identification of direct downstream RA target genes across tissues is lacking
  • Human genetic disease association through causative mutations not established in primary literature

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016491 oxidoreductase activity 4
Localization
GO:0005783 endoplasmic reticulum 2 GO:0005739 mitochondrion 1 GO:0005811 lipid droplet 1
Pathway
R-HSA-1266738 Developmental Biology 5 R-HSA-1430728 Metabolism 4 R-HSA-9709957 Sensory Perception 2
Partners
ALDH1A2CRABP2CRALBPCRBP1LRATRPE65

Evidence

Reading pass · 14 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2007 RDH10 is a short-chain dehydrogenase/reductase that catalyzes the oxidation of retinol to retinal (first step of retinoic acid synthesis); a point mutation in the trex mouse abolishes this enzymatic activity, leading to insufficient RA signaling and embryonic defects in craniofacial, limb, and organ development. ENU forward genetic screen, protein modeling, enzymatic assays, mutant embryo analysis Genes & development High 17473173
2004 RDH10 functions as an all-trans retinol dehydrogenase localized to the microsomal (membrane) fraction of retinal Müller cells, using NADP+ as its preferred cofactor to generate all-trans retinal. Western blot, immunohistochemistry, RT-PCR, HPLC-based enzymatic activity assay on microsomal fractions, cofactor preference determination Investigative ophthalmology & visual science High 15505029
2008 Human RDH10 is a strictly NAD+-dependent enzyme (not NADP+-dependent as initially reported) with the lowest apparent Km for all-trans-retinol (~0.035 µM) among NAD+-dependent retinoid oxidoreductases; it also accepts cis-retinols as substrates and functions exclusively in the oxidative direction in cells, increasing retinaldehyde and retinoic acid levels. siRNA-mediated silencing of RDH10 in human cells significantly decreases RA production from retinol. Kinetic enzyme assays, siRNA knockdown, retinoid quantification The Journal of biological chemistry High 18502750
2009 RDH10 oxidizes 11-cis-retinol to 11-cis-retinaldehyde in vitro (enhanced by CRALBP); physically interacts with CRALBP and RPE65 as shown by co-immunoprecipitation; co-localizes with RPE65 and CRALBP in bovine RPE cells; and can reconstitute the visual cycle chromophore 11-cis-retinaldehyde from all-trans-retinol when co-expressed with RPE65, LRAT, and CRALBP. In vitro enzymatic assay, reconstitution in HEK-293A cells, co-immunoprecipitation, immunocytochemistry, HPLC retinoid profiling Investigative ophthalmology & visual science High 19458327
2011 RDH10 is the primary retinol dehydrogenase responsible for the first step of embryonic vitamin A oxidation; this step occurs predominantly in a membrane-bound cellular compartment, which prevents inhibition by cytosolic CRBP1 (RBP1), and widely-expressed cytosolic RDH enzymes play only a minor role under normal dietary conditions. Rdh10(trex) mutant embryos, dietary retinaldehyde supplementation rescue experiments, RDH activity assays, subcellular fractionation Developmental biology High 21782811
2011 RDH10 is required for interdigital RA signaling and subsequent interdigital tissue loss, but is not required for limb patterning (Meis2/Shh expression and skeletal patterning remain normal in Rdh10 mutants); RA activity in Rdh10 mutants is detected in neuroectoderm but not limbs during initiation and patterning. Rdh10(trex/trex) mutant analysis, RARE-lacZ RA reporter transgene, RA rescue treatment, in situ hybridization, skeletal staining Developmental dynamics High 21360789
2012 Rdh10 associates predominantly with mitochondria/mitochondrial-associated membrane (MAM) in the absence of lipid droplet biosynthesis, but redistributes to lipid droplets during acyl ester biosynthesis; the 32 N-terminal residues (hydrophobic region plus net positive charge) are required for lipid droplet targeting, while both N-terminal and 48 C-terminal hydrophobic residues are required for mitochondria/MAM targeting and protein stability. Subcellular fractionation, live-cell imaging/colocalization, domain deletion analysis, colocalization with CRBP1 and LRAT The Journal of biological chemistry High 23155051
2013 RDH10 is a required component of a PPARγ-directed linear pathway for ATRA synthesis in human dendritic cells, acting upstream of RALDH2 and CRABP2; all three proteins are regulated by PPARγ and are necessary for ATRA production induced by PPARγ activation. siRNA knockdown, ATRA quantification, PPARγ agonist treatment, expression analysis in human mo-DCs and murine DC subsets Journal of lipid research Medium 23833249
2018 Rdh10 catalyzes the first step of atRA biosynthesis postnatally; embryonic fibroblasts with Rdh10 knockout show decreased atRA biosynthesis and increased adipogenesis, reversed by atRA or RAR pan-agonist treatment; Rdh10 heterozygote mice show modestly reduced tissue atRA with increased adiposity and metabolic defects, establishing RDH10 as physiologically essential for atRA-mediated metabolic control. Rdh10 heterozygote and knockout mouse models, atRA quantification by LC-MS, adipogenesis assays, in vivo metabolic phenotyping, pharmacological rescue with atRA Diabetes High 29321172
2017 RDH10 is specifically required in non-neural crest cells prior to E10.5 for proper choanae formation; loss of Rdh10 leads to ectopic Fgf8 expression in the nasal fin, decreased cell proliferation and increased cell death in nasal cavity epithelium, causing choanal atresia. Conditional/tissue-specific Rdh10 mutant mouse analysis, in situ hybridization for Fgf8, cell proliferation and apoptosis assays Human molecular genetics High 28169399
2018 RDH10-mediated retinoic acid signaling is required for submandibular salivary gland initiation; RA signaling acts through RARα specifically (not other RAR isoforms); Rdh10 and Aldh1a2 are co-expressed in SMG mesenchyme at the site of gland initiation. Ex vivo SMG initiation assay, Rdh10 conditional loss-of-function, RAR isoform-specific pharmacological analysis, expression localization Development High 29986869
2019 RDH10-mediated retinoic acid signaling is required for spontaneous fetal mouth movement; Rdh10-deficient embryos display mispatterned pharyngeal nerves and skeletal elements that block fetal mouth movement in utero, leading to cleft palate via a biomechanical mechanism. Stage-specific Rdh10 inactivation, X-ray microtomography, in utero ultrasound video, ex vivo culture, tissue staining Disease models & mechanisms High 31300413
2025 Rdh10-mediated RA signaling is required for vagal neural crest cell (NCC) invasion into the foregut to form the enteric nervous system; Rdh10 loss-of-function causes intestinal aganglionosis; Rdh10 expression in mesenchyme surrounding the foregut entrance is essential between E7.5-E9.5; RNA-seq revealed downregulation of the Ret-Gdnf-Gfrα1 signaling network and altered extracellular matrix (increased collagen deposition) in Rdh10 mutants, restricting NCC entry. Rdh10 loss-of-function mouse embryos, comparative RNA-seq, NCC lineage tracing, collagen staining bioRxivpreprint Medium 39896510
2025 Rdh10-derived RA directly activates Alx1 transcription via an RA response element (RARE) near the Alx1 locus, as demonstrated by decreased H3K27ac at the Alx1 locus and decreased Alx1 expression in Rdh10-/- eye tissue; Alx1 knockout recapitulates the optic cup formation defect seen in Rdh10 knockouts, placing Alx1 as a direct downstream RA target gene in eye development. ChIP-seq (H3K27ac), RNA-seq on Rdh10-/- eye tissue, RARE identification, in situ hybridization, CRISPR/Cas9 Alx1 knockout bioRxivpreprint Medium bio_10.1101_2025.06.24.661406

Source papers

Stage 0 corpus · 19 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2007 RDH10 is essential for synthesis of embryonic retinoic acid and is required for limb, craniofacial, and organ development. Genes & development 272 17473173
2011 RDH10 is the primary enzyme responsible for the first step of embryonic Vitamin A metabolism and retinoic acid synthesis. Developmental biology 63 21782811
2004 Identification of RDH10, an All-trans Retinol Dehydrogenase, in Retinal Muller Cells. Investigative ophthalmology & visual science 60 15505029
2009 The 11-cis-retinol dehydrogenase activity of RDH10 and its interaction with visual cycle proteins. Investigative ophthalmology & visual science 57 19458327
2008 Kinetic analysis of human enzyme RDH10 defines the characteristics of a physiologically relevant retinol dehydrogenase. The Journal of biological chemistry 57 18502750
2011 Rdh10 mutants deficient in limb field retinoic acid signaling exhibit normal limb patterning but display interdigital webbing. Developmental dynamics : an official publication of the American Association of Anatomists 53 21360789
2007 Expression of the murine retinol dehydrogenase 10 (Rdh10) gene correlates with many sites of retinoid signalling during embryogenesis and organ differentiation. Developmental dynamics : an official publication of the American Association of Anatomists 48 17849458
2018 Modest Decreases in Endogenous All-trans-Retinoic Acid Produced by a Mouse Rdh10 Heterozygote Provoke Major Abnormalities in Adipogenesis and Lipid Metabolism. Diabetes 42 29321172
2012 The retinol dehydrogenase Rdh10 localizes to lipid droplets during acyl ester biosynthesis. The Journal of biological chemistry 41 23155051
2012 Morphological defects in a novel Rdh10 mutant that has reduced retinoic acid biosynthesis and signaling. Genesis (New York, N.Y. : 2000) 36 22162152
2008 Dynamic expression of the retinoic acid-synthesizing enzyme retinol dehydrogenase 10 (rdh10) in the developing mouse brain and sensory organs. The Journal of comparative neurology 32 18399539
2017 Rdh10 loss-of-function and perturbed retinoid signaling underlies the etiology of choanal atresia. Human molecular genetics 25 28169399
2013 RDH10, RALDH2, and CRABP2 are required components of PPARγ-directed ATRA synthesis and signaling in human dendritic cells. Journal of lipid research 24 23833249
2010 The expression of Stra6 and Rdh10 in the avian embryo and their contribution to the generation of retinoid signatures. The International journal of developmental biology 20 20563989
2018 RDH10-mediated retinol metabolism and RARα-mediated retinoic acid signaling are required for submandibular salivary gland initiation. Development (Cambridge, England) 19 29986869
2007 Forced expression of RDH10 gene retards growth of HepG2 cells. Cancer biology & therapy 15 17218779
2019 RDH10 function is necessary for spontaneous fetal mouth movement that facilitates palate shelf elevation. Disease models & mechanisms 14 31300413
2003 Genomic organization and transcription of the human retinol dehydrogenase 10 (RDH10) gene. FEBS letters 9 14596915
2025 Rdh10-mediated Retinoic Acid Signaling Regulates the Neural Crest Cell Microenvironment During ENS Formation. bioRxiv : the preprint server for biology 2 39896510