Dlx5, short for distal-less homeobox 5, is a crucial transcription factor. It is essential for initiating osteoblast differentiation by driving Runt-related transcription factor 2 expression [1,4]. It is also involved in the regulation of multiple biological processes and associated with various pathways. In the context of adipocyte-osteoblast lineage divergence, Dlx5 physically binds to peroxisome proliferator-activated receptor gamma (PPARγ), repressing its transcriptional activity, which may be relevant for managing diabetes drug-mediated obesity [1].

In mouse models, targeted deletion of Dlx5/6 in GABAergic neurons (Dlx5/6VgatCre mice) shows that Dlx5/6 expression levels linearly correlate with the density of parvalbumin-positive neurons in the adult prelimbic cortex and hippocampus, as well as the intensity of anxiety and compulsivity-like behaviors [2]. In the study of split-hand-foot malformation (SHFM1) associated with deafness, disruption of exonic enhancers of Dlx5/6 genes in 7q21 region, rather than the Dlx5/6 genes themselves, was found to be responsible for the phenotype [3]. In osteosarcoma, knockdown of Dlx5 in cell lines inhibited cell growth and progression, while overexpression had the opposite effect, and this was attributed to the activation of the NOTCH signaling pathway [4]. In osteoarthritis, anti-Dlx5 treatment retarded the disease progression by downregulating chondrocyte hypertrophy and apoptosis-related genes [5]. In renal cell carcinoma, silencing Dlx5 reduced cell proliferation, induced apoptosis, decreased radioresistance and increased DNA damage, with Dlx5 promoting radioresistance through upregulation of c-Myc [6].

In conclusion, Dlx5 plays diverse and essential functions in multiple biological processes such as osteoblast differentiation, neuronal development, and organogenesis. The use of mouse models, especially those with targeted deletion or modification of Dlx5, has been instrumental in revealing its role in various disease conditions including neuropsychiatric disorders, congenital malformations, bone-related cancers, osteoarthritis, and renal cell carcinoma. These findings provide valuable insights into potential therapeutic targets for these diseases.

References:

1. Kim, Chae Yul, Cho, Dong Hyeok, Chung, Dong Jin, Han, Younho, Lee, Kwang Youl. . Dlx5 Represses the Transcriptional Activity of PPARγ. In Biological & pharmaceutical bulletin, 44, 1303-1308. doi:10.1248/bpb.b21-00245. https://pubmed.ncbi.nlm.nih.gov/34471058/

2. Aouci, Rym, El Soudany, Mey, Maakoul, Zakaria, Levi, Giovanni, Narboux-Nême, Nicolas. 2022. Dlx5/6 Expression Levels in Mouse GABAergic Neurons Regulate Adult Parvalbumin Neuronal Density and Anxiety/Compulsive Behaviours. In Cells, 11, . doi:10.3390/cells11111739. https://pubmed.ncbi.nlm.nih.gov/35681437/

3. Ambrosetti, Irene, Bernardini, Laura, Pollazzon, Marzia, Novelli, Antonio, Garavelli, Livia. 2023. Split Hand-Foot and Deafness in a Patient with 7q21.13-q21.3 Deletion Not Including the DLX5/6 Genes. In Genes, 14, . doi:10.3390/genes14081526. https://pubmed.ncbi.nlm.nih.gov/37628577/

4. Zhang, Xiaojing, Bian, Huiqin, Wei, Wei, Cai, Cheguo, Zheng, Qiping. 2021. DLX5 promotes osteosarcoma progression via activation of the NOTCH signaling pathway. In American journal of cancer research, 11, 3354-3374. doi:. https://pubmed.ncbi.nlm.nih.gov/34249467/

5. Lu, Ye, Zhang, Chengyuan, Jiang, Shilin, Yuan, Feng. 2022. Anti-Dlx5 Retards the Progression of Osteoarthritis through Inhibiting Chondrocyte Hypertrophy and Apoptosis. In Evidence-based complementary and alternative medicine : eCAM, 2022, 5019920. doi:10.1155/2022/5019920. https://pubmed.ncbi.nlm.nih.gov/35280506/

6. Hu, Danfei, Li, Mingyao, Chen, Xiaodong. . DLX5 Promotes Radioresistance in Renal Cell Carcinoma by Upregulating c-Myc Expression. In Frontiers in bioscience (Landmark edition), 29, 400. doi:10.31083/j.fbl2911400. https://pubmed.ncbi.nlm.nih.gov/39614438/