Mdga2, short for MAM domain containing glycosylphosphatidylinositol anchor 2, is a significant synaptic organizer. It contributes to synapse organization by inhibiting the formation of the synaptogenic neuroligin-neurexin complex, acting as a synaptic repressor, especially at inhibitory synapses [1,3]. MDGA2 is also involved in regulating the balance of excitatory and inhibitory neural connections, which is crucial for normal brain function [2]. Genetic mouse models have been essential for studying its functions.

In KO/CKO mouse models, Mdga2 deficiency leads to various consequences. Conditional deletion of Mdga2 in CA1 pyramidal neurons of adult mice upregulated glutamatergic synapses, neuronal excitability, and impaired memory and social affiliation, suggesting its role in optimizing hippocampal circuits for plasticity, cognition, and social behaviors [3]. Mdga2+/- mice showed delayed development of motor, grip strength, and exploratory behavior, indicating non-social phenotypes related to neurodevelopmental disorders [4]. Additionally, in gastric cancer, MDGA2 acts as a tumour suppressor, with its promoter hypermethylation being associated with decreased patient survival [5].

In summary, Mdga2 is vital for synaptic development and function, and its dysregulation is linked to neurodevelopmental disorders and cancer. Mouse models, especially KO/CKO models, have been instrumental in uncovering its role in these biological processes and disease conditions, providing insights into potential therapeutic targets for related diseases.

References:

1. Bemben, Michael A, Sandoval, Matthew, Le, Aliza A, Nicoll, Roger A, Diaz-Alonso, Javier. 2023. Contrastsing synaptic roles of MDGA1 and MDGA2. In bioRxiv : the preprint server for biology, , . doi:10.1101/2023.05.25.542333. https://pubmed.ncbi.nlm.nih.gov/37720016/

2. Loh, Ken H, Stawski, Philipp S, Draycott, Austin S, Carr, Steven A, Ting, Alice Y. . Proteomic Analysis of Unbounded Cellular Compartments: Synaptic Clefts. In Cell, 166, 1295-1307.e21. doi:10.1016/j.cell.2016.07.041. https://pubmed.ncbi.nlm.nih.gov/27565350/

3. Wang, Xuehui, Lin, Donghui, Jiang, Jie, Connor, Steven A, Xie, Yicheng. 2024. MDGA2 Constrains Glutamatergic Inputs Selectively onto CA1 Pyramidal Neurons to Optimize Neural Circuits for Plasticity, Memory, and Social Behavior. In Neuroscience bulletin, 40, 887-904. doi:10.1007/s12264-023-01171-1. https://pubmed.ncbi.nlm.nih.gov/38321347/

4. Fertan, Emre, Wong, Aimée A, Montbrun, Thalia S Garvock-de, Yamamoto, Tohru, Brown, Richard E. 2023. Early postnatal development of the MDGA2+/- mouse model of synaptic dysfunction. In Behavioural brain research, 452, 114590. doi:10.1016/j.bbr.2023.114590. https://pubmed.ncbi.nlm.nih.gov/37499910/

5. Wang, Kunning, Liang, Qiaoyi, Li, Xiaoxing, Sung, Joseph J Y, Yu, Jun. 2015. MDGA2 is a novel tumour suppressor cooperating with DMAP1 in gastric cancer and is associated with disease outcome. In Gut, 65, 1619-31. doi:10.1136/gutjnl-2015-309276. https://pubmed.ncbi.nlm.nih.gov/26206665/