Gene Expression and Histopathological Changes in the Placenta of the Serotonin Transporter (Slc6a4) Knockout Mouse Suggest a Role for Serotonin in Controlling Nutrient Acquisition

We report the application of single-molecule-based sequencing technology for high-throughput profiling in 5-HT transporter SLC6A4 gene knockout 12.5 dpc mouse placenta. This study was to test the hypothesis that ablation of the Slc6a4 gene would result in morphological changes correlated with defined gene expression changes in the placenta. We found that Slc6a4 KO placentas had a much increased pTGC to spongiotrophoblast area ratio relative to WT placentas. Slc6a4 KO placentas had significantly elevated expression of genes associated with intestinal functions such as nutrient sensing, uptake, and catabolism, and blood clotting. Integrative correlation analyses revealed that upregulation of many of these genes was correlated with the expansion of the pTGC layer. One other key gene in this module was dopa decarboxylase (Ddc), which catalyzes the conversion of L-5-hydroxytryptophan to 5-HT. Our studies suggest a new paradigm relating to how 5-HT operates in the placenta, namely as a factor regulating metabolic functions and blood clotting through autocrine actions. We further suggest that the pTGC are functional analogs of the enterochromaffin 5-HT-positive cells of the gut, which have roles in controlling similar activities within the intestinal mucosa. Our studies suggest a new paradigm in thinking about how 5-HT acts in the placenta, namely not so much as a classic neurotransmitter but as an endocrine factor regulating metabolic functions and blood clotting through autocrine actions. Overall design: Placental mRNA profiles of 12.5 dpc wild type (WT) and Slc6a4 -/- mice