Negr1, or neuronal growth regulator 1, is a GPI-anchored cell adhesion molecule in the immunoglobulin LON family. It has been implicated in regulating neurite outgrowth and synapse formation, and is involved in multiple biological pathways, with its role being studied in relation to various diseases. Genetic models, especially knockout mouse models, have been crucial in understanding its functions [1,4,5,6,7,8].

In Negr1-deficient (negr1-/-) mice, anxiety-and depression-like behaviors increased, along with decreased adult hippocampal neurogenesis, compromised LTP and mEPSC in the dentate gyrus, and reduced lipocalin-2 (Lcn2) expression in the hippocampus. Heterologous Lcn2 expression in the hippocampal DG of negr1-/-mice rescued these behavioral and physiological deficits [1]. In addition, negr1-/-mice showed impaired affective discrimination, aberrant olfactory habituation, and decreased adult neurogenesis in the subventricular zone [4]. Moreover, Negr1-/-male mice had alterations in monoaminergic neurotransmission and enhanced time-dependent sensitization to amphetamine [7]. In the context of other diseases, in colorectal cancer, the miR-122/NEGR1 axis affects cancer cell proliferation, invasion, and macrophage polarization through the PI3K/AKT pathway [2]. In neuroblastoma, Negr1 is downregulated, and its overexpression or treatment with Negr1-derived peptides can halt tumor progression by triggering ALK degradation [3]. In the salivary gland, Negr1 knockout mice had decreased pilocarpine-and carbachol-induced salivation, suggesting its role in muscarinic Ca2 + signaling [6].

In conclusion, Negr1 plays essential roles in regulating adult hippocampal and olfactory neurogenesis, affective behaviors, monoaminergic neurotransmission, and also impacts cancer progression and salivary secretion. The use of Negr1 knockout mouse models has significantly contributed to understanding its functions in depression, autism-related behaviors, neuroblastoma, and colorectal cancer, among others, providing valuable insights into the underlying molecular mechanisms and potential therapeutic targets.

References:

1. Noh, Kyungchul, Lee, Hyunkyoung, Choi, Tae-Yong, Choi, Se-Young, Lee, Sung Joong. 2019. Negr1 controls adult hippocampal neurogenesis and affective behaviors. In Molecular psychiatry, 24, 1189-1205. doi:10.1038/s41380-018-0347-3. https://pubmed.ncbi.nlm.nih.gov/30651602/

2. Dai, Shipeng, Zhuang, Haiwen, Li, Zhuozheng, Chai, Yue, Zhou, Qing. 2024. miR-122/NEGR1 axis contributes colorectal cancer liver metastasis by PI3K/AKT pathway and macrophage modulation. In Journal of translational medicine, 22, 1060. doi:10.1186/s12967-024-05901-5. https://pubmed.ncbi.nlm.nih.gov/39587606/

3. Pischedda, Francesca, Ghirelli, Alessia, Tripathi, Vasvi, Piccoli, Giovanni. 2023. Negr1-Derived Peptides Trigger ALK Degradation and Halt Neuroblastoma Progression In Vitro and In Vivo. In Pharmaceutics, 15, . doi:10.3390/pharmaceutics15092307. https://pubmed.ncbi.nlm.nih.gov/37765276/

4. Kim, Kwang Hwan, Noh, Kyungchul, Lee, Jaesung, Lee, Soojin, Lee, Sung Joong. 2024. NEGR1 Modulates Mouse Affective Discrimination by Regulating Adult Olfactory Neurogenesis. In Biological psychiatry global open science, 4, 100355. doi:10.1016/j.bpsgos.2024.100355. https://pubmed.ncbi.nlm.nih.gov/39170714/

5. Carboni, Lucia, Pischedda, Francesca, Piccoli, Giovanni, Mathé, Aleksander A, Domenici, Enrico. 2020. Depression-Associated Gene Negr1-Fgfr2 Pathway Is Altered by Antidepressant Treatment. In Cells, 9, . doi:10.3390/cells9081818. https://pubmed.ncbi.nlm.nih.gov/32751911/

6. Lee, Jisoo, Kim, Soohyun, Lee, Boram, Park, Hee-Kyung, Choi, Se-Young. 2023. Major depression-related factor NEGR1 controls salivary secretion in mouse submandibular glands. In iScience, 26, 106773. doi:10.1016/j.isci.2023.106773. https://pubmed.ncbi.nlm.nih.gov/37216094/

7. Kaare, Maria, Jayaram, Mohan, Jagomäe, Toomas, Philips, Mari-Anne, Vasar, Eero. 2022. Depression-Associated Negr1 Gene-Deficiency Induces Alterations in the Monoaminergic Neurotransmission Enhancing Time-Dependent Sensitization to Amphetamine in Male Mice. In Brain sciences, 12, . doi:10.3390/brainsci12121696. https://pubmed.ncbi.nlm.nih.gov/36552158/

8. Szczurkowska, Joanna, Pischedda, Francesca, Pinto, Bruno, Piccoli, Giovanni, Cancedda, Laura. . NEGR1 and FGFR2 cooperatively regulate cortical development and core behaviours related to autism disorders in mice. In Brain : a journal of neurology, 141, 2772-2794. doi:10.1093/brain/awy190. https://pubmed.ncbi.nlm.nih.gov/30059965/