Lpar1, encoding the endothelial differentiation gene-2 receptor (Edg2), is a lysophosphatidic acid (LPA) receptor. It couples to G protein-coupled receptors (GPCRs) and is involved in regulating cell proliferation, migration, survival, and apoptosis [1]. Present in almost all human tissues, it is most abundant in the brain. The LPA-Lpar1 signaling pathway is of great biological importance, being associated with multiple physiological and pathological processes. Genetic models, such as gene knockout (KO) and conditional knockout (CKO) mouse models, have been instrumental in studying Lpar1's functions.

Constitutive Lpar1 null mutant mice have been used to identify the role of LPA-Lpar1 signaling in neurobiological processes, brain development, behavior, and neuropathic pain modeling [4]. Lpar1 deletion causes neurodevelopmental disorders and central nervous system (CNS) diseases like brain cancer, neuropsychiatric disorders, demyelination diseases, and neuropathic pain [1]. In the enteric nervous system, LPAR1 is enriched in enteric glia, and its blockade in mice attenuates gastrointestinal motility and causes enteric neuro-and gliopathy, while samples from humans with chronic intestinal pseudo-obstruction show reduced glial LPAR1 expression [3]. In neuroblastoma, decreased LPAR1 expression promotes tumor cell migration, and the LPA-LPAR1 axis has tumor-suppressing effects [2]. In liver fibrosis, LPAR1 is a therapeutic target on collagen-producing central vein-associated hepatic stellate cells (CaHSCs), and its blockade inhibits liver fibrosis in a rodent NASH model [5].

In conclusion, Lpar1 plays crucial roles in various biological processes, especially in the CNS, enteric nervous system, and in cancer and fibrosis development. KO and CKO mouse models have been vital in revealing these functions, highlighting Lpar1 as a potential therapeutic target for multiple diseases including CNS disorders, chronic intestinal pseudo-obstruction, neuroblastoma, and liver fibrosis.

References:

1. Xiao, Dongqiong, Su, Xiaojuan, Gao, Hu, Li, Xihong, Qu, Yi. 2021. The Roles of Lpar1 in Central Nervous System Disorders and Diseases. In Frontiers in neuroscience, 15, 710473. doi:10.3389/fnins.2021.710473. https://pubmed.ncbi.nlm.nih.gov/34385905/

2. Liu, Xiangjun, Pei, Mengmiao, Yu, Yongbo, Wang, Xiaolin, Gui, Jingang. 2022. Reduction of LPAR1 Expression in Neuroblastoma Promotes Tumor Cell Migration. In Cancers, 14, . doi:10.3390/cancers14143346. https://pubmed.ncbi.nlm.nih.gov/35884407/

3. Ahmadzai, Mohammad M, McClain, Jonathon L, Dharshika, Christine, De Giorgio, Roberto, Gulbransen, Brian D. . LPAR1 regulates enteric nervous system function through glial signaling and contributes to chronic intestinal pseudo-obstruction. In The Journal of clinical investigation, 132, . doi:10.1172/JCI149464. https://pubmed.ncbi.nlm.nih.gov/35166239/

4. Rivera, Richard R, Lin, Mu-En, Bornhop, Emily C, Chun, Jerold. 2020. Conditional Lpar1 gene targeting identifies cell types mediating neuropathic pain. In FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 34, 8833-8842. doi:10.1096/fj.202000317R. https://pubmed.ncbi.nlm.nih.gov/32929779/

5. Dobie, Ross, Wilson-Kanamori, John R, Henderson, Beth E P, Marioni, John C, Henderson, Neil C. . Single-Cell Transcriptomics Uncovers Zonation of Function in the Mesenchyme during Liver Fibrosis. In Cell reports, 29, 1832-1847.e8. doi:10.1016/j.celrep.2019.10.024. https://pubmed.ncbi.nlm.nih.gov/31722201/