TIAM2S as a novel regulator for serotonin level enhances brain plasticity and locomotion behavior

Abstract

Abbreviations: CA3, cornu ammonis 3; Cdc42, cell division control protein 42 homolog; DG, dentate gyrus; GEF, guanine nucleotide exchange factor; GFAP, glial fibrillary acidic protein; HTR1B, 5-hydroxytryptamine receptor 1B; MAP-2, microtubule-associated protein 2; PARP, poly (ADP-ribose) polymerase; PDGF, platelet-derived growth factor; Rac1, Ras-related C3 botulinum toxin substrate 1; RhoA, Ras homolog gene family member A; STEF, SIF and Tiam1-like exchange factor; TIAM1/2, T cell lymphoma invasion and metastasis1/2. ABSTRACTTIAM2S, the short form of human T-cell lymphoma invasion and metastasis 2, can have oncogenic effects when aberrantly expressed in the liver or lungs. However, it is also abundant in healthy, non-neoplastic brain tissue, in which its primary function is still unknown. Here, we examined the neurobiological and behavioral significance of human TIAM2S using the human brain protein panels, a human NT2/D1-derived neuronal cell line model (NT2/N), and transgenic mice that overexpress human TIAM2S (TIAM2S-TG). Our data reveal that TIAM2S exists primarily in neurons of the restricted brain areas around the limbic system and in well-differentiated NT2/N cells. Functional studies revealed that TIAM2S has no guanine nucleotide exchange factor (GEF) activity and is mainly located in the nucleus. Furthermore, whole-transcriptome and enrichment analysis with total RNA sequencing revealed that TIAM2S-knockdown (TIAM2S-KD) was strongly associated with the cellular processes of the brain structural development and differentiation, serotonin-related signaling, and the diseases markers representing neurobehavioral developmental disorders. Moreover, TIAM2S-KD cells display decreased neurite outgrowth and reduced serotonin levels. Moreover, TIAM2S overexpressing TG mice show increased number and length of serotonergic fibers at early postnatal stage, results in higher serotonin levels at both the serum and brain regions, and higher neuroplasticity and hyperlocomotion in latter adulthood. Taken together, our results illustrate the nononcogenic functions of human TIAM2S and demonstrate that TIAM2S is a novel regulator of serotonin level, brain neuroplasticity, and locomotion behavior. K E Y W O R D Sguanine nucleotide exchange factor (GEF), hyperlocomotion, neuroplasticity, serotonergic fiber, serotonin (5-HT), TIAM2 3268 | CHU et al. | 3269CHU et al.

TIAM2S Mediates Serotonin Homeostasis and Provokes a Pro-Inflammatory Immune Microenvironment Permissive for Colorectal Tumorigenesis

“…TIAM2S has been shown to act as oncogene in liver and lung cancer development. To characterize the systemic effect of TIAM2S on tumorigenesis, we generated pan-expression of TIAM2S mouse lines [ 9 ]. Five independent clones were identified by Southern blot analysis, and two female and one male F1 progeny were used to generate subsequent offspring.…”

“…TIAM2S-TG mice were grossly normal at birth [ 9 ] and gain weight at about the same rate as the WT littermates up to 12 months of age. At the age of ~2 years old, several TIAM2S-TG mice showed abdominal masses.…”

“…Previous publications demonstrate that serotonin activates immune cells to produce pro-inflammatory mediators and results in gut inflammation (review see [ 21 ]). Our recent work revealed that TIAM2S functions as a novel regulator of cellular serotonin and that TIAM2S-TG mice exhibit higher serum serotonin levels than WT animals [ 9 ]. As TIAM2S-TG mice developed significantly higher proportions of infiltrative lymphocyte and tumors in various organs, we evaluated whether TIAM2S-mediated serotonin expression in the immune response may lead to inflammation profiles differing from those of aged WT animals.…”

“…It was found that the accumulated IL-23/IL-17A axis located in colonic TLOs from TG mice ( Figure 4 B, left), and the presence of positive cell staining are both elevated in inflamed colonic tissues from the TG mice compared to the WT mice ( Figure 4 B, right, IL-17A, p < 0.001; IL-23, p < 0.001). Collectively, ectopic TIAM2S expression promotes chronic inflammation through an increase in serotonin level and triggers CD8+ T lymphocytes to develop IBD through the interleukin (IL)-23/IL-17 axis [ 9 ].…”

“…Recently, we found that TIAM2S is normally produced in the neurons of restricted brain regions and uncovered its non-oncogenic functions as a novel regulator of serotonin level, brain neuroplasticity, and locomotion behavior [ 9 ]. Furthermore, we identified that SP1 binds directly to the GC box located in the TIAM2S core promoter and controls TIAM2S ectopic expression in liver cancer cells [ 10 ].…”