Lnx1, short for Ligand of NUMB Protein X1, is an E3 ubiquitin ligase. It is known for its interaction with NUMB, a cell fate determinant protein, and is thought to modulate NUMB/NOTCH signalling, which is crucial in processes like cortical neurogenesis [1]. Additionally, via its four PDZ domains, it binds to numerous other proteins, suggesting roles in the nervous system such as synapse formation, neurotransmission, and regulation of neuroglial function. It also has implications in non-neuronal processes including embryonic patterning, pancreas development in zebrafish, and potential involvement in mammalian colorectal cancer, osteoclast differentiation, and immune function [1].

Gene knockout studies have provided insights into Lnx1's functions. In double knockout mice lacking Lnx1 and Lnx2 in the CNS, an anxiety-related phenotype was observed, indicating its role in the regulation of anxiety-like behaviors [1]. In cancer research, Lnx1 knockout (KO) in p53 wild-type cancer cells (A549, HCT116, and MCF7) led to increased p53 stability and activation of p53-dependent transcription, suggesting Lnx1 contributes to tumor growth by inhibiting p53-dependent signaling [2]. In glioblastoma, knocking down Lnx1 reversed the expansion of glioma stem cells (GSCs) promoted by temozolomide therapy, as Lnx1-regulated Notch1 signaling was found to contribute to stemness and therapeutic resistance [5]. In the nervous system, Lnx1 deficiency in mice led to hippocampal subregional disorder in neuronal activity, social memory impairments, and defective synaptic function due to NMDA receptor hypofunction and disruption of the Lnx1-NMDAR-EphB2 complex [3]. Also, Lnx1 deficiency in mice caused abnormal dendritic spine development and impaired synaptogenesis, as loss of Lnx1 promoted internalization of EphB receptors [4].

In conclusion, Lnx1 plays essential roles in multiple biological processes. Through gene knockout models, its significance in regulating anxiety-like behaviors, tumor growth, and neural functions such as social memory and synaptogenesis has been revealed. These findings contribute to understanding the mechanisms underlying related diseases and potentially developing new therapeutic strategies.

References:

1. Young, Paul W. 2018. LNX1/LNX2 proteins: functions in neuronal signalling and beyond. In Neuronal signaling, 2, NS20170191. doi:10.1042/NS20170191. https://pubmed.ncbi.nlm.nih.gov/32714586/

2. Park, Rackhyun, Kim, Hyunju, Jang, Minsu, Jang, Ik-Soon, Park, Junsoo. 2019. LNX1 contributes to tumor growth by down-regulating p53 stability. In FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 33, 13216-13227. doi:10.1096/fj.201900366R. https://pubmed.ncbi.nlm.nih.gov/31533005/

3. Liu, Xian-Dong, Ai, Peng-Hui, Zhu, Xiao-Na, Sun, Suya, Xu, Nan-Jie. 2019. Hippocampal Lnx1-NMDAR multiprotein complex mediates initial social memory. In Molecular psychiatry, 26, 3956-3969. doi:10.1038/s41380-019-0606-y. https://pubmed.ncbi.nlm.nih.gov/31772302/

4. Li, Na, Chen, Si, Xu, Nan-Jie, Chen, Jin-Jin, Liu, Xian-Dong. 2022. Scaffold Protein Lnx1 Stabilizes EphB Receptor Kinases for Synaptogenesis. In Frontiers in molecular neuroscience, 15, 861873. doi:10.3389/fnmol.2022.861873. https://pubmed.ncbi.nlm.nih.gov/35531068/

5. Baisiwala, Shivani, Hall, Robert R, Saathoff, Miranda R, Horbinski, Craig M, Ahmed, Atique U. 2020. LNX1 Modulates Notch1 Signaling to Promote Expansion of the Glioma Stem Cell Population during Temozolomide Therapy in Glioblastoma. In Cancers, 12, . doi:10.3390/cancers12123505. https://pubmed.ncbi.nlm.nih.gov/33255632/