Abstract
Serotonin regulates numerous processes in the mammary gland. Our objective was to discover novel genes, pathways and functions which serotonin modulates during lactation. The rate limiting enzyme in the synthesis of non-neuronal serotonin is tryptophan-hydroxylase (TPH1). Therefore, we used TPH1 deficient dams (KO; serotonin deficient, n = 4) and compared them to wild-type (WT; n = 4) and rescue (RC; KO + 100 mg/kg 5-hydroxytryptophan injected daily, n = 4) dams. Mammary tissues were collected on day 10 of lactation. Total RNA extraction, amplification, library preparation and sequencing were performed following the Illumina mRNA-Seq. Overall, 97 and 204 genes (false discovery rate, FDR ≤ 0.01) exhibited a minimum of a 2-fold expression difference between WT vs. KO and WT vs. RC dams, respectively. Most differentially expressed genes were related to calcium homeostasis, apoptosis regulation, cell cycle, cell differentiation and proliferation, and the immune response. Additionally, gene set enrichment analysis using Gene Ontology and Medical Subject Headings databases revealed the alteration of several biological processes (FDR ≤ 0.01) including fat cell differentiation and lipid metabolism, regulation of extracellular signal-related kinase and mitogen-activated kinase cascades, insulin resistance, nuclear transport, membrane potential regulation, and calcium release from the endoplasmic reticulum into the cytosol. The majority of the biological processes and pathways altered in the KO dams are central for mammary gland homeostasis. Increasing peripheral serotonin in the RC dams affects specific pathways that favor lactation. Our data confirms the importance of serotonin during lactation in the mammary gland.
Highlights
Serotonin (5-hydroxytryptamine, 5-HT) is a monoamine that is biochemically derived from the essential amino acid L-tryptophan
Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in serotonin synthesis and converts L-tryptophan into 5-hydroxy-L-tryptophan (5-HTP) which is converted to serotonin
Pregnant dams were assigned to 1 of 3 groups: group 1 consisted of Tph1 deficient dams (KO, n = 4), group 2 consisted of Tph1-KO mice injected daily (i.p.) with 100 mg/kg of 5-HTP to rescue peripheral serotonin function, and group 3 consisted of wild-type dams (WT, n = 4)
Summary
Serotonin (5-hydroxytryptamine, 5-HT) is a monoamine that is biochemically derived from the essential amino acid L-tryptophan. Serotonin is largely known for its role as a neurotransmitter in the CNS, where 2% of total serotonin is produced. There is increasing evidence supporting the role of non-neuronal (peripheral) serotonin, which accounts for 98% of total serotonin in the body, in physiological functions and metabolic processes [5,6]. Peripheral serotonin acts through more than 15 different receptors that possess unique spatiotemporal distribution [7]. This enables the possibility for multiple, simultaneous physiological outcomes that can be attributed to serotonin across and within tissues
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