Differential patterning of genes involved in serotonin metabolism and transport in extra-embryonic tissues of the mouse

Abstract

Introduction Serotonin (5-HT) is an important neuromodulator, but recently has been shown to be involved in neurodevelopment. Although previous studies have demonstrated that the placenta is a major source of forebrain 5-HT during early forebrain development, the processes of how 5-HT production, metabolism, and transport from placenta to fetus are regulated are unknown. As an initial step in determining the mechanisms involved, we investigated the expression patterns of genes critical for 5-HT system function in mouse extraembryonic tissues. Methods Mid- through late gestation expression of 5-HT system-related enzymes, Tph1, Ddc, Maoa, and 5-HT transporters, Sert/Slc6a4, Oct3/Slc22a3, Vmat2/Slc18a2, and 5-HT in placenta and yolk sac were examined, with cell type-specific resolution, using multiplex fluorescent in situ hybridization to co-localize transcripts and immunocytochemistry to co-localize the corresponding proteins and neurotransmitter. Results Tph1 and Ddc are found in the syncytiotrophoblast I (SynT-I) and sinusoidal trophoblast giant cells (S-TGC), whereas Maoa is expressed in SynT-I, syncytiotrophoblast II (SynT-II) and S-TGC. Oct3 expression is observed in the SynT-II only, while Vmat2 is mainly expressed in S-TGC. Surprisingly, there were comparatively high expression of Tph1, Ddc, and Maoa in the yolk sac visceral endoderm. Discussion In addition to trophoblast cells, visceral endoderm cells in the yolk sac may contribute to fetal 5-HT production. The findings raise the possibility of a more complex regulation of 5-HT access to the fetus through the differential roles of trophoblasts that surround maternal and fetal blood space and of yolk sac endoderm prior to normal degeneration.

Sculpting Cerebral Cortex with Serotonin in Rodent and Primate

“…After P7, the expression of MAOB is largely predominant in 5-HT+ neurons [126]. MAOs are also expressed by many non-aminergic structures, in particular the placenta and in a subpopulation of VZ-SVZ cells ( [126,127] and our unpublished results) where they may regulate the amount of 5-HT locally. Interestingly, MAOs expression and protein synthesis are tightly regulated and have been shown to be sensitive to environmental factors such as inflammation and ischaemia-like conditions [34].…”

“…The placenta (syncytiothrophoblastic cells and sinusoidal throphoblastic giant cells) of the placenta contain Tph1, AADC and MAO [124,125,127], and convert tryptophan of maternal origin into 5-HT as soon as E10-E11 [150]. Homozygote knock-out embryos in which 5-HT neurons fail to fully differentiate or to produce normal amounts of 5-HT levels do not display severe cortical defects when gestating in heterozygous dams.…”

Impact of Maternal Serotonin Transporter Genotype on Placental Serotonin, Fetal Forebrain Serotonin, and Neurodevelopment

“…Within the placenta, SERT is present in the labrynth zone, where cells are of fetal origin, and this expression reaches high levels only later in development (~E17.5; Wu et al, 2016). This suggests that increased maternal SERT function indirectly affects placental handling and storage of 5-HT.…”

“…As maternal 5-HT cannot cross the placenta into fetal circulation (Bonnin et al, 2011;Robson and Senior, 1964), it is unlikely that changes in maternal 5-HT blood levels would directly affect placental or fetal forebrain 5-HT levels. Syncytiotrophoblasts, the cellular interface between the maternal and fetal blood supply in the placenta, are thought to tightly regulate free 5-HT via MAOA degradation (Wu et al, 2016). Owing to technical limitations, we were unable to measure 5-HT turnover in the placenta.…”

Specific Connectivity and Unique Molecular Identity of MET Receptor Tyrosine Kinase Expressing Serotonergic Neurons in the Caudal Dorsal Raphe Nuclei

“…For in situ hybridization, fresh whole brains from P7, 14, and adult mice were dissected by rapidly frozen by submersion in ice-cold isopentane as described 44, 55 .…”