Tph1-KO Mouse

Tph1, short for tryptophan hydroxylase 1, is a rate-limiting enzyme in serotonin synthesis. It is mainly expressed by specialized gut endocrine cells (enterochromaffin cells) and other non-neuronal cell types like adipocytes [3]. Serotonin, synthesized from tryptophan by Tph1, is involved in multiple physiological functions, such as mood regulation, sleep, anxiety control, and gastrointestinal motility regulation. It also plays a role in glucose homeostasis and adiposity [3].

In research on depression, berberine was found to improve depressive symptoms in CUMS-stimulated mice by activating Tph1, promoting tryptophan biotransformation into serotonin and inhibiting the kynurenine metabolism pathway [1]. A meta-analysis suggested that the A218C polymorphism of Tph1 gene could be a possible risk factor for suicide behavior [2]. In bladder cancer, overexpression of Tph1 declined cell survival and inhibited tumorigenesis via the HIF-1α pathway [4]. In CD8+ T cells within the tumor microenvironment, a high level of IL-2 can induce Tph1 expression, leading to T cell exhaustion [5]. Glutamine was shown to increase Tph1 mRNA stability via the p38 mitogen-activated kinase in mouse mastocytoma cells [6]. In pancreatic ductal adenocarcinoma, overexpression of Tph1 was related to gemcitabine resistance and the survival of cancer stem cells [7].

In conclusion, Tph1 is crucial for serotonin synthesis and is involved in multiple biological processes and disease conditions. Studies, including those using genetic models (implied by polymorphism and gene-related functional studies), have revealed its role in depression, suicide behavior, bladder cancer, T cell exhaustion, and pancreatic cancer, among others. These findings contribute to our understanding of the molecular mechanisms underlying these diseases and may provide potential therapeutic targets.

References:

1. Ge, Ping-Yuan, Qu, Shu-Yue, Ni, Sai-Jia, Zhang, Qi-Chun, Zhu, Hua-Xu. 2022. Berberine ameliorates depression-like behavior in CUMS mice by activating TPH1 and inhibiting IDO1-associated with tryptophan metabolism. In Phytotherapy research : PTR, 37, 342-357. doi:10.1002/ptr.7616. https://pubmed.ncbi.nlm.nih.gov/36089660/

2. Genis-Mendoza, Alma Delia, Hernández-Díaz, Yazmín, González-Castro, Thelma Beatriz, Ramos-Méndez, Miguel Ángel, Nicolini, Humberto. 2022. Association between TPH1 polymorphisms and the risk of suicide behavior: An updated meta-analysis of 18,398 individuals. In Frontiers in psychiatry, 13, 932135. doi:10.3389/fpsyt.2022.932135. https://pubmed.ncbi.nlm.nih.gov/35928776/

3. Jones, Lauren A, Sun, Emily W, Martin, Alyce M, Keating, Damien J. 2020. The ever-changing roles of serotonin. In The international journal of biochemistry & cell biology, 125, 105776. doi:10.1016/j.biocel.2020.105776. https://pubmed.ncbi.nlm.nih.gov/32479926/

4. Ren, Jianwei, Mo, Zhiting, Deng, Xia, Jin, Jie, Zhang, Huihui. 2024. TPH1 inhibits bladder tumorigenesis by targeting HIF-1α pathway in bladder cancer. In Asian biomedicine : research, reviews and news, 18, 171-179. doi:10.2478/abm-2024-0023. https://pubmed.ncbi.nlm.nih.gov/39309474/

5. Liu, Yuying, Zhou, Nannan, Zhou, Li, Xiao-Feng Qin, F, Huang, Bo. 2021. IL-2 regulates tumor-reactive CD8+ T cell exhaustion by activating the aryl hydrocarbon receptor. In Nature immunology, 22, 358-369. doi:10.1038/s41590-020-00850-9. https://pubmed.ncbi.nlm.nih.gov/33432230/

6. Park, Heeyoung, Lee, Chang-Wook, Kang, Jieun, Sadra, Ali, Huh, Sung-Oh. 2022. Glutamine increases stability of TPH1 mRNA via p38 mitogen-activated kinase in mouse mastocytoma cells. In Molecular biology reports, 50, 267-277. doi:10.1007/s11033-022-07693-7. https://pubmed.ncbi.nlm.nih.gov/36331742/

7. Chaudhary, Prakash, Guragain, Diwakar, Chang, Jae-Hoon, Kim, Jung-Ae. 2021. TPH1 and 5-HT7 Receptor Overexpression Leading to Gemcitabine-Resistance Requires Non-Canonical Permissive Action of EZH2 in Pancreatic Ductal Adenocarcinoma. In Cancers, 13, . doi:10.3390/cancers13215305. https://pubmed.ncbi.nlm.nih.gov/34771469/