RasGRP1, a Ras guanine nucleotide exchange factor, is an essential regulator of lymphocyte receptor signaling. It functions as a diacylglycerol (DAG)-regulated nucleotide exchange factor, activating RAS by exchanging bound GDP for GTP, with wide-ranging downstream cellular effects. It is involved in various signaling pathways and is crucial for the development, expression, and regulation of immune cells [3]. Genetic models, such as gene knockout mouse models, have been valuable for studying its functions.

In mice, Rasgrp1 deletion leads to defective T lymphocyte development [1]. RasGRP1-deficient patients suffer from immune deficiency, and the gene has been linked to autoimmunity. In C57BL/6 mice, diminished Rasgrp1 expression caused defective T lymphocyte selection, and the severity of inflammatory disease inversely correlated with Rasgrp1 expression levels. In autoimmune patients, active inflammation correlated with decreased RASGRP1 levels in CD4+ T cells [1]. RasGRP1 also plays roles in other conditions. For example, in psoriasis mouse models, RasGRP1 deficiency and overexpression influence imiquimod-induced psoriasis-like manifestations and skin inflammation, and VEGF mediates psoriatic inflammation through the RasGRP1-AKT-NF-κB pathway [2]. In Parkinson's disease mouse and macaque models, l-DOPA treatment up-regulated RasGRP1 in the striatum, and RasGRP1 -/- mice had diminished l-DOPA-induced dyskinesia (LID) without affecting l-DOPA's therapeutic effects [4].

In conclusion, RasGRP1 is vital for lymphocyte receptor signaling and T lymphocyte development. Studies using gene knockout mouse models have revealed its significance in autoimmunity, psoriasis, and Parkinson's disease-related LID. Understanding RasGRP1's functions provides insights into the underlying mechanisms of these diseases and may offer potential therapeutic targets.

References:

1. Baars, Matthijs J D, Douma, Thera, Simeonov, Dimitre R, Roose, Jeroen P, Vercoulen, Yvonne. 2020. Dysregulated RASGRP1 expression through RUNX1 mediated transcription promotes autoimmunity. In European journal of immunology, 51, 471-482. doi:10.1002/eji.201948451. https://pubmed.ncbi.nlm.nih.gov/33065764/

2. Mao, Yiwen, Ge, Huiyao, Chen, Weiwei, Li, Bao, Sun, Liangdan. 2023. RasGRP1 influences imiquimod-induced psoriatic inflammation via T-cell activation in mice. In International immunopharmacology, 122, 110590. doi:10.1016/j.intimp.2023.110590. https://pubmed.ncbi.nlm.nih.gov/37429143/

3. Fan, Shangzhi, Kang, Bo, Li, Shaoqian, Chen, Danjun, Zhou, Jiecan. 2024. Exploring the multifaceted role of RASGRP1 in disease: immune, neural, metabolic, and oncogenic perspectives. In Cell cycle (Georgetown, Tex.), 23, 722-746. doi:10.1080/15384101.2024.2366009. https://pubmed.ncbi.nlm.nih.gov/38865342/

4. Eshraghi, Mehdi, Ramírez-Jarquín, Uri Nimrod, Shahani, Neelam, Usiello, Alessandro, Subramaniam, Srinivasa. 2020. RasGRP1 is a causal factor in the development of l-DOPA-induced dyskinesia in Parkinson's disease. In Science advances, 6, eaaz7001. doi:10.1126/sciadv.aaz7001. https://pubmed.ncbi.nlm.nih.gov/32426479/