Snai2, also known as Slug, is an evolutionarily conserved C2H2 zinc finger protein encoded by the SNAI2 gene. It is a transcription factor that orchestrates biological processes crucial to tissue development and tumorigenesis, initially recognized as an epithelial-to-mesenchymal transition (EMT) transcription factor. Snai2 is involved in a wide range of biological processes like tumor metastasis, stem cell biology, cellular differentiation, vascular remodeling, and DNA damage repair, mainly through facilitating epigenetic regulation of transcriptional programs [2].

In mice, hepatocyte-specific deletion of both Snai1 and Snai2 (but not one alone) suppresses liver cyclin A2/D1 expression and regenerative hepatocyte proliferation after hepatectomy or CCl4 treatments, while augmenting CCl4-stimulated hepatic stellate cell (HSC) activation and liver fibrosis. Conversely, Snai2 overexpression in the liver enhances hepatocyte replication and suppresses liver fibrosis after CCl4 treatment, suggesting that hepatic Snai2 promotes liver regeneration and suppresses fibrosis [1]. In rhabdomyosarcoma (RMS), SNAI2 ablation using Nuclease technology led to the loss of most FN-RMS cells, and the few surviving clones recovered NOTCH1 expression. Also, SNAI2 knockdown increased the expression of the pro-apoptotic gene BIM, identifying a p53-independent SNAI2/BIM signaling axis relevant to radiation treatment in RMS [4,5]. In bone marrow (BM), germline or MSPC-selective Snai2 deletion reduces the functional MSPC pool and impairs HSC niche function, with Snai2 maintaining BM niche cells by repressing osteopontin expression [3].

In conclusion, Snai2 is a critical regulator in multiple biological processes. Gene knockout and conditional knockout mouse models have been instrumental in revealing its role in liver regeneration and fibrosis, rhabdomyosarcoma development and response to radiation, and maintenance of bone marrow niche cells. These model-based studies provide insights into the mechanisms underlying these biological processes and diseases, potentially guiding future therapeutic strategies [1,3,4,5].

References:

1. Wang, Pingping, Kang, Qianqian, Wu, Wen-Shu, Rui, Liangyou. 2024. Hepatic Snai1 and Snai2 promote liver regeneration and suppress liver fibrosis in mice. In Cell reports, 43, 113875. doi:10.1016/j.celrep.2024.113875. https://pubmed.ncbi.nlm.nih.gov/38451818/

2. Zhou, Wenhui, Gross, Kayla M, Kuperwasser, Charlotte. 2019. Molecular regulation of Snai2 in development and disease. In Journal of cell science, 132, . doi:10.1242/jcs.235127. https://pubmed.ncbi.nlm.nih.gov/31792043/

3. Wei, Qiaozhi, Nakahara, Fumio, Asada, Noboru, Guo, Wenjun, Frenette, Paul S. 2020. Snai2 Maintains Bone Marrow Niche Cells by Repressing Osteopontin Expression. In Developmental cell, 53, 503-513.e5. doi:10.1016/j.devcel.2020.04.012. https://pubmed.ncbi.nlm.nih.gov/32413329/

4. Sreenivas, Prethish, Wang, Long, Wang, Meng, Stanton, Benjamin Z, Ignatius, Myron S. 2023. A SNAI2/CTCF Interaction is Required for NOTCH1 Expression in Rhabdomyosarcoma. In Molecular and cellular biology, 43, 547-565. doi:10.1080/10985549.2023.2256640. https://pubmed.ncbi.nlm.nih.gov/37882064/

5. Wang, Long, Hensch, Nicole R, Bondra, Kathryn, Houghton, Peter J, Ignatius, Myron S. 2021. SNAI2-Mediated Repression of BIM Protects Rhabdomyosarcoma from Ionizing Radiation. In Cancer research, 81, 5451-5463. doi:10.1158/0008-5472.CAN-20-4191. https://pubmed.ncbi.nlm.nih.gov/34462275/