Bin1-KO Mouse

BIN1, also known as bridging integrator 1 and amphiphysin-2, belongs to the BIN1/amphiphysin/RVS167 (BAR) superfamily. It plays crucial roles in membrane dynamics, participating in processes like endocytosis, membrane cycling, and cytoskeletal regulation [2,5]. It is also involved in DNA repair deficiency, cell-cycle arrest, and apoptosis [2]. The gene is associated with various diseases including Alzheimer's disease, cancer, myopathy, heart failure, and inflammation [2,5]. Genetic models, such as gene knockout (KO) and conditional knockout (CKO) mouse models, have been instrumental in studying BIN1's functions.

In Alzheimer's disease, BIN1 knockdown in cortical neurons led to increased Aβ accumulation due to BACE1 accumulation at enlarged early endosomes, and BIN1 deficiency impaired its interaction with tau, elevating tau phosphorylation [3]. In microglia, Bin1 knockdown regulated the activation of pro-inflammatory and disease-associated responses, and microglia-specific Bin1 CKO in vivo revealed its role in regulating disease-associated gene expression and counteracting CX3CR1 signaling [1]. In mouse hippocampal neurons, Bin1 knockdown via RNAi reduced dendritic arbor size, and autophagy inhibition mitigated this effect, suggesting that BIN1 may be involved in autophagy-related cognitive impairment [4]. In cardiomyocytes, BIN1 is involved in transverse tubule (t-tubule) formation and function. BIN1 knockdown in aging male mouse hearts restored cardiac systolic function, while overexpression of BIN1 in aging hearts was associated with dysregulated endosomal recycling and disrupted trafficking of cardiac channels [6,7].

In conclusion, BIN1 is essential in multiple biological processes, particularly in membrane-related functions. Model-based research, especially KO and CKO mouse models, has significantly contributed to understanding its role in diseases such as Alzheimer's disease, cardiac-related disorders, and microglial-mediated inflammation. These studies provide insights into potential therapeutic targets for these diseases.

References:

1. Sudwarts, Ari, Ramesha, Supriya, Gao, Tianwen, Thinakaran, Gopal, Rangaraju, Srikant. 2022. BIN1 is a key regulator of proinflammatory and neurodegeneration-related activation in microglia. In Molecular neurodegeneration, 17, 33. doi:10.1186/s13024-022-00535-x. https://pubmed.ncbi.nlm.nih.gov/35526014/

2. Chen, Si-Yu, Cao, Jin-Long, Li, Kun-Peng, Wan, Shun, Yang, Li. 2023. BIN1 in cancer: biomarker and therapeutic target. In Journal of cancer research and clinical oncology, 149, 7933-7944. doi:10.1007/s00432-023-04673-7. https://pubmed.ncbi.nlm.nih.gov/36890396/

3. Kaur, Ishnoor, Behl, Tapan, Sundararajan, G, Gulati, Monica, Chigurupati, Sridevi. 2023. BIN1 in the Pursuit of Ousting the Alzheimer's Reign: Impact on Amyloid and Tau Neuropathology. In Neurotoxicity research, 41, 698-707. doi:10.1007/s12640-023-00670-3. https://pubmed.ncbi.nlm.nih.gov/37847429/

4. Jin, Yuxi, Zhao, Lin, Zhang, Yanli, Xiao, Ming, Sheng, Chengyu. 2024. BIN1 deficiency enhances ULK3-dependent autophagic flux and reduces dendritic size in mouse hippocampal neurons. In Autophagy, 21, 223-242. doi:10.1080/15548627.2024.2393932. https://pubmed.ncbi.nlm.nih.gov/39171951/

5. Giraud, Quentin, Laporte, Jocelyn. 2024. Amphiphysin-2 (BIN1) functions and defects in cardiac and skeletal muscle. In Trends in molecular medicine, 30, 579-591. doi:10.1016/j.molmed.2024.02.005. https://pubmed.ncbi.nlm.nih.gov/38514365/

6. Perdreau-Dahl, Harmonie, Lipsett, David B, Frisk, Michael, Morth, J Preben, Louch, William E. 2023. BIN1, Myotubularin, and Dynamin-2 Coordinate T-Tubule Growth in Cardiomyocytes. In Circulation research, 132, e188-e205. doi:10.1161/CIRCRESAHA.122.321732. https://pubmed.ncbi.nlm.nih.gov/37139790/

7. Westhoff, Maartje, Del Villar, Silvia G, Voelker, Taylor L, Dickson, Eamonn J, Dixon, Rose E. 2024. BIN1 knockdown rescues systolic dysfunction in aging male mouse hearts. In Nature communications, 15, 3528. doi:10.1038/s41467-024-47847-8. https://pubmed.ncbi.nlm.nih.gov/38664444/