Dlx2, a member of the Distal-less family genes, is a transcription factor that plays crucial roles in multiple biological processes. It is involved in neural development, osteogenic differentiation, and may be associated with immune-related responses in certain cancers. In neural development, it is related to the conversion of astrocytes to neurons and generation of GABAergic neurons. In osteogenic differentiation, it is linked to the Wnt/β-catenin pathway and activation of genes promoting osteoblast maturation. It may also be associated with the remodeling of the tumor microenvironment in lung squamous cell carcinoma [1,4,5,6,7].

In the context of neural regeneration, overexpression of Dlx2 can convert mouse striatal astrocytes into neurons in a dose-dependent manner, specifically into DARPP32+ and Ctip2+ medium spiny neurons. However, in the white matter, its overexpression may lead to partial reprogramming of astrocytes associated with neuroinflammation, which can be suppressed by NeuroD1 [1]. In osteosarcoma, knockdown of DLX2 inhibits tumor proliferation and migration in vitro and tumor growth in vivo, as it enhances the repression of CDH2 transcription by binding to HOXC8, promoting epithelial-mesenchymal transition and doxorubicin resistance [2]. Osteocyte-derived exosomal DLX2 alleviates IL-1β-induced cartilage repair and inactivates the Wnt pathway in osteoarthritis [3]. In hBMSCs, DLX2 activates Wnt1 transcription and mediates the Wnt/β-catenin signal to promote osteogenic differentiation [4]. In mice, overexpression of Dlx2 in neural crest cells causes transcriptome changes in maxillary prominences, restricts cell proliferation, and causes precocious differentiation in mesenchymal cells during craniofacial development [5].

In summary, Dlx2 is a multifunctional transcription factor. Its role in neural development, especially in astrocyte-to-neuron conversion, and in osteogenic processes has been well-demonstrated through various in vivo studies including those using mouse models. Its abnormal regulation is associated with diseases such as osteosarcoma and potentially with immune-related prognosis in lung squamous cell carcinoma, highlighting its importance in understanding disease mechanisms and developing potential therapies [1,2,3,4,5,6].

References:

1. Liu, Min-Hui, Xu, Yu-Ge, Bai, Xiao-Ni, Xu, Liang, Chen, Gong. 2024. Efficient Dlx2-mediated astrocyte-to-neuron conversion and inhibition of neuroinflammation by NeuroD1. In Developmental neurobiology, 84, 274-290. doi:10.1002/dneu.22951. https://pubmed.ncbi.nlm.nih.gov/39034481/

2. Zhang, Boya, Du, Xinhui, Fan, Yichao, Zhao, Ruiying, Yao, Weitao. 2023. DLX2 promotes osteosarcoma epithelial-mesenchymal transition and doxorubicin resistance by enhancing HOXC8-CDH2 axis. In iScience, 26, 108272. doi:10.1016/j.isci.2023.108272. https://pubmed.ncbi.nlm.nih.gov/38026218/

3. Xu, Wenjuan, Zhang, Yuanyuan, Li, Lijuan, Zhi, Shenshen, Li, Wei. 2024. Osteocyte-derived exosomes regulate the DLX2/wnt pathway to alleviate osteoarthritis by mediating cartilage repair. In Autoimmunity, 57, 2364686. doi:10.1080/08916934.2024.2364686. https://pubmed.ncbi.nlm.nih.gov/38946534/

4. Zeng, Xiao, Wang, Yong, Dong, Qiang, Ma, Min-Xian, Liu, Xing-De. 2020. DLX2 activates Wnt1 transcription and mediates Wnt/β-catenin signal to promote osteogenic differentiation of hBMSCs. In Gene, 744, 144564. doi:10.1016/j.gene.2020.144564. https://pubmed.ncbi.nlm.nih.gov/32165291/

5. Sun, Jian, Zhang, Jianfei, Bian, Qian, Wang, Xudong. 2023. Effects of Dlx2 overexpression on the genes associated with the maxillary process in the early mouse embryo. In Frontiers in genetics, 14, 1085263. doi:10.3389/fgene.2023.1085263. https://pubmed.ncbi.nlm.nih.gov/36891149/

6. Huang, Liling, Xie, Tongji, Zhao, Fuqiang, Han, Xiaohong, Shi, Yuankai. 2022. DLX2 Is a Potential Immune-Related Prognostic Indicator Associated with Remodeling of Tumor Microenvironment in Lung Squamous Cell Carcinoma: An Integrated Bioinformatical Analysis. In Disease markers, 2022, 6512300. doi:10.1155/2022/6512300. https://pubmed.ncbi.nlm.nih.gov/36317140/

7. Yang, Nan, Chanda, Soham, Marro, Samuele, Südhof, Thomas C, Wernig, Marius. 2017. Generation of pure GABAergic neurons by transcription factor programming. In Nature methods, 14, 621-628. doi:10.1038/nmeth.4291. https://pubmed.ncbi.nlm.nih.gov/28504679/