*3.1.1. ALDH1A1*

*ALDH1A1* encodes a homotetramer that is ubiquitously distributed in the adult epithelia of several organs such as brain, testis, kidney, eye lens, retina, liver and lungs. ALDH1A1 takes its position among the three highly-conserved cytosolic isozymes (see ALDH1A2 and ALDH1A3), which catalyze the oxidation of the retinol metabolite, retinal (retinaldehyde), to RA. ALDH1A1 has great affinity for the oxidation of both all-*trans*-(*K*m < 0.1 μM) and 9 *cis*-retinal. By serving as a ligand for nuclear RA receptors (RAR) and retinoid X receptors (RXR), RA regulates gene expression; therefore its synthesis is crucial for normal growth, differentiation, development and the maintenance of adult epithelia in vertebrate animals. In retinoid-dependent tissues (including the retina), retinal-oxidizing ALDHs have been shown to display differential expression patterns during organogenesis in rodents, reflecting that RA signaling is indeed important for embryogenesis. The *in vivo* function of ALDH1A1 in RA synthesis is proven by the fact that after retinol treatment, while *Aldh1a1*−/−mice are viable and possess normal morphology of the retina, the livers of *Aldh1a1*−/<sup>−</sup> mice have reduced RA synthesis and increased serum retinal levels. Surprisingly, it appeared that *Aldh1a1*−/<sup>−</sup> mice are protected against both diet-induced obesity and insulin resistance and this demonstrates that retinal might regulate the metabolic response to highfat diets transcriptionally, and that the *ALDH1A1* could be a candidate gene for therapeutic targeting. Supression of *ALDH1A1* in cultured hepatocytes reduces both the omegaoxidation of free fatty acids and the production of reactive oxygen species (ROS). Liver ALDH1A1 levels were shown to be decreased in *RXR*α−/<sup>−</sup> mice, which suggests that RA binding is an activating factor in *ALDH1A1* gene expression. The androgen receptor might also be included in modulation of ALDH1A1, which is recognized to be an androgen binding protein. RA is required for testicular development and *ALDH1A1* is absent in genital tissues of humans with androgen receptor-negative testicular feminization. ALDH1A1 is significantly expressed in dopaminergic neurons that are known to require RA for their differentiation and development in the human brain. In these neurons, *ALDH1A1* is under the control of Pitx3, a homeodomain transcription factor that, possibly through *ALDH1A1* upregulation, regulates the particularization and maintenance of disassociated populations of dopaminergic neurons. Decreased levels of ALDH1A1 takes place in dopaminergic neurons of the substantia nigra of patients with Parkinson's disease (PD), as well as the ventral tegmental area in schizophrenic patients. In the central nervous system (CNS), monoamine oxidase (MAO) metabolizes dopamine to aldehyde, as it's metabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL), which growing evidence suggests might be neurotoxic, and it may lead to cell death in relation to neurological pathologies when accumulated. In maintaining low intraneuronal levels of DOPAL, ALDH1A1 may undertake a critical role by catalyzing its metabolism to 3,4-dihydroxyphenylacetic acid (DOPAC). Being one of 139 genes that are differentially expressed in primary human HSCs, and through the production of RA, ALDH1A1 has been shown to promote their differentiation.

These data suggest that for the therapeutic amplification of HSCs, ALDH1A1 inhibition could potentially be used (Marchitti*, et al.*, 2008, Moore*, et al.*, 2009).
