HTR2A is a Gq protein-coupled receptor that could potentially affect multi-ple intracellular signaling pathways. The expansion of the neocortex (Ncx), which in humans is the site of our cognitive abilities, is thought to primarily be due to an increase in neuron production. Neuron production and Ncx size are governed by the abundance and proliferative capacity of neural progenitor cells (NPCs) during embryonic/fetal development. The interaction of NPCs with their environment during cortical development constitutes a key aspect affecting BP abundance and proliferative capacity, diverse cell-extrinsic signals that may regulate BP proliferation have increasingly become the focus of research. These signals, including growth factors, extracellular structural components, hormones, and neurotransmitters, et al. Among the neurotransmitters, serotonin (5-HT) emerges as an interesting target of study to be potentially involved in BP proliferation. Therefore, studying the specific function of the 5-HT receptor HTR2A plays a key role in evolution-related functions, and the use of specific HTR2A antibodies is essential in this process.
In 12–13 wpc human aRG and bRG, the HTR2A mRNA level was the highest when compared to the other HTR family members. In contrast, HTR2A mRNA was virtually absent (FPKM < 0.5) in all the Ncx zones and isolated cell populations of E14.5 mouse Ncx analyzed. Such an expression pattern, with higher levels in NPCs (germinal zones) and lower levels in neurons (cortical plate) in F-human Ncx and a virtual absence in E-mouse Ncx, was not observed for any other neurotransmitter receptor analyzed. Next, we examined the distribution of HTR2A protein in E mice, E-ferrets, and F-human Ncx by immunofluorescence using HTR2A antibody. This immunofluorescence signal was specific because it was not observed in the absence of primary anti-HTR2A antibody, and the results were consistent with mRNA expression data. The latter HTR2A antibody selectively recognized the HTR2A protein upon immunoblotting of a total homogenate of F-human Ncx, further corroborating its specificity. The results showed that the expansion of the Ncx in humans and ferrets as compared to mice, may be linked to the expression and function of HTR2A.
There are two major signaling pathways downstream of activated HTR2A. First is the canonical pathway in which activated HTR2A causes activation of the heterotrimeric G protein Gq and the Gqa subunit then activates phospholipase C. This in turn results in the generation of diacylglycerol and inositol trisphosphate and consequently in the activation of protein kinase C, which then stimulates MEK to phosphorylate ERK1/2. This eventually leads to increased cell proliferation. Second is a non-canonical pathway in which activated HTR2A triggers the phosphorylation of the EGFR. This involves the interaction of EGF with the EGFR, a condition that would be fulfilled for F-human Ncx BPs as our analyses of previously published transcriptome datasets revealed EGF expression in these NPCs. The thus activated EGFR eventually induces, via several intermediate steps, the phosphorylation of ERK1/2, which then leads to increased cell proliferation. The data show that the activated HTR2A-induced BP proliferation is mediated via the second pathway involving the EGFR2 acting upstream of ERK1/2.
The findings not only demonstrate that 5-HT activation of HTR2A results in a high abundance of proliferative BPs but also imply that this effect of activated HTR2A is of relevance in the context of the evolutionary expansion of the Ncx. It suggests that the placenta-derived 5-HT, acting via activation of HTR2A, may have exerted a key role in cortical development in species exhibiting a relatively large Ncx. It suggests that the placenta-derived 5-HT, acting via activation of HTR2A, may have exerted a key role in cortical development in species exhibiting a relatively large Ncx.
In conclusion, HTR2A is Highly Expressed in E-Ferret and F-Human Ncx was demonstrated by the application of HTR2A antibodies and founded a role of human HTR2A in bRG morphology and on the other hand add another facet to the role of HTR2A in the developing Ncx. The study uncovers a hitherto unknown facet involved in the expansion of the Ncx during development. Importantly, it should be noted that aberrant 5-HT signaling and disturbed expression or mutation of HTR2A have been observed in various neurodevelopmental and psychiatric disorders, such as Down syndrome, attention-deficit/hyperactivity disorder, and autism. The findings on the involvement of HER2 and ERK1/2 in activated HTR2A-induced BP proliferation in F-human Ncx may help explain how aberrant HTR2A signaling during fetal brain development can lead to congenital disorders and may suggest novel approaches for therapeutic avenues.
| Target | Cat. No. | Product Name | Host | Isotype | Application | |
| HTR2A | DPABH-02369 | Rabbit anti-Human 5HT2A Receptor polyclonal antibody | Rabbit | IgG | IHC-P | Inquiry |
| CABT-B1419 | Anti-HTR2A monoclonal antibody, clone 0C22.2 | Mouse | IgG2a, κ | WB, IHC | Inquiry |
| Target | Cat. No. | Product Name | Expression System | Tag/Conjugate | Application | |
| HTR2A | CDBP1526 | Human HTR2A blocking peptide | N/A | Unconjugated | Apuri, BL, ELISA | Inquiry |
| Target | Cat. No. | Product Name | Size | Species Reactivity | Application | Detection Sample | |
| HTR2A | DEIA-LL159 | Human HTR2A ELISA Kit | 96T | Human | Quantitative | Serum, plasma, tissue homogenates and other biological fluids | Inquiry |
