Aldh1a2, also known as aldehyde dehydrogenase 1 family member A2, is a rate-limiting enzyme responsible for the synthesis of retinoic acid from vitamin A [1-4, 8-10]. The retinoic acid synthetic pathway it mediates is involved in numerous biological processes, including embryonic development, immune regulation, and cell differentiation [1, 4-5]. Genetic models such as gene knockout (KO) and conditional knockout (CKO) mouse models can be valuable tools to study its functions [1].

In kidney-related research, Aldh1a2 expression in glomerular parietal epithelial cells (PECs) was found to be associated with various kidney diseases. For example, its expression was increased in anti-glomerular basement membrane glomerulonephritis and ischemia-reperfusion acute kidney injury mouse models, while decreased in chronic kidney disease models [1]. In ovarian cancer, functional studies showed that forced expression of ALDH1A2 impaired the proliferation and invasive activity of cancer cells, suggesting it might act as a tumor suppressor [2]. In osteoarthritis, ALDH1A2 risk variants were associated with hand OA, and boosting retinoic acid synthesis by using talarozole, a retinoic acid metabolism blocking agent, could suppress inflammation in articular cartilage [3]. In spinal muscular atrophy, knockdown of Aldh1a2 in primary spinal motor neuron cultures led to neurodegeneration, and Aldh1a2 could rescue the pathological features in SMA mouse embryo-derived motor neurons [4]. In spermatogenesis, global deletion of Aldh1a1 and Aldh1a2 genes blocked spermatogenesis, indicating the requirement of retinoic acid synthesis by Sertoli cells for spermatogonial differentiation [5].

In conclusion, Aldh1a2 is essential for retinoic acid synthesis and plays crucial roles in multiple biological processes. KO/CKO mouse models have revealed its significance in diseases like kidney diseases, ovarian cancer, osteoarthritis, spinal muscular atrophy, and spermatogenesis-related disorders. These findings help us understand the underlying mechanisms of these diseases and may provide potential therapeutic targets.

References:

1. Liu, Wen-Bin, Fermin, Damian, Xu, An-Long, Kopp, Jeffrey B, Xu, Qihe. 2024. Single-cell RNA sequencing data locate ALDH1A2-mediated retinoic acid synthetic pathway to glomerular parietal epithelial cells. In Experimental biology and medicine (Maywood, N.J.), 249, 10167. doi:10.3389/ebm.2024.10167. https://pubmed.ncbi.nlm.nih.gov/39360029/

2. Choi, Jung-A, Kwon, Hyunja, Cho, Hanbyoul, Hewitt, Stephen M, Kim, Jae-Hoon. 2019. ALDH1A2 Is a Candidate Tumor Suppressor Gene in Ovarian Cancer. In Cancers, 11, . doi:10.3390/cancers11101553. https://pubmed.ncbi.nlm.nih.gov/31615043/

3. Zhu, Linyi, Kamalathevan, Pragash, Koneva, Lada A, Giele, Henk, Shirley, Rebecca. 2022. Variants in ALDH1A2 reveal an anti-inflammatory role for retinoic acid and a new class of disease-modifying drugs in osteoarthritis. In Science translational medicine, 14, eabm4054. doi:10.1126/scitranslmed.abm4054. https://pubmed.ncbi.nlm.nih.gov/36542696/

4. Kataoka, Mayumi, Sahashi, Kentaro, Tsujikawa, Koyo, Iida, Madoka, Katsuno, Masahisa. 2023. Dysregulation of Aldh1a2 underlies motor neuron degeneration in spinal muscular atrophy. In Neuroscience research, 194, 58-65. doi:10.1016/j.neures.2023.04.007. https://pubmed.ncbi.nlm.nih.gov/37146794/

5. Topping, Traci, Griswold, Michael D. 2022. Global Deletion of ALDH1A1 and ALDH1A2 Genes Does Not Affect Viability but Blocks Spermatogenesis. In Frontiers in endocrinology, 13, 871225. doi:10.3389/fendo.2022.871225. https://pubmed.ncbi.nlm.nih.gov/35574006/