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The serotonin receptor 5-HT2B has been shown to be critically important during embryogenesis as the knockout of this gene in mice causes heart defects and embryonic lethality that impairs further analyses on other embryonic cell and tissue types. In the present review, we highlight how the use of Xenopus laevis, an alternative vertebrate model suitable for gene loss and gain of function analyses, has contributed to our understanding of the role of 5-HT2B signaling during development. In vivo studies showed that 5-HT2B signaling is not only required for heart development, but that it also has a crucial role in ocular and craniofacial morphogenesis, being involved in shaping the first branchial arch and the jaw joint, in retinogenesis and possibly in periocular mesenchyme development. These findings may be relevant for our understanding of congenital defects including human birth malformations. In addition, 5-HT2B appears to be required for the therapeutic actions of selective serotonin reuptake inhibitors commonly prescribed as antidepressant drugs to pregnant and lactating women. We discuss how the understanding of the molecular basis of serotonin signaling in a suitable animal embryogenesis model may open new lines of investigations and therapies in humans.
Fig. 1. Xenopus laevis as a model system to study gene function. On the left, the life cycle of Xenopus laevis. On the right, the gene loss of function strategy that specifically blocks the translation of a gene of interest by microinjecting spe- cific morpholino oligos in one side of the embryo. Antisense morpholino is targeted to se- quences close to the translation start site. The injected side is visualized by the co-injection of a reporter mRNA such as LacZ or GFP. Examples of chromogenic reaction for beta galactosidase (red) and GFP (green fluorescence) are shown in neural stage embryos.
Fig. 2. Neural crest cell transplantation assay. Top: Scheme of the cranial NCCs transplant assay at neurula stage (st. 16). (A,B,C) Lateral views of an early tailbud (stage 28) transplanted embryo: (A) bright field; (B) GFP fluorescence in transplanted cranial NCCs; (C) merge.
Fig. 3. Visualization of serotonergic cells during Xenopus embryogenesis. Distribution of serotonergic cells in Xenopus larvae, as detected in cryostat sections by immunostaining with an anti-serotonin antibody. Left panel, upper row: sagittal section of a late tailbud (stage 35) larva showing serotonin cells in the raphe nuclei (arrow); middle row, from left to right: serotonergic cells are found in the retina (amacrine cells), in the raphe nuclei, and in the skin of a late tailbud (stage 42) larva. Right panel: coronal section showing serotonin cells detected in the gut of a stage 49tadpole (red fluorescence). Coronal planes are indicated as a, b, c.
Fig. 4. Role of serotonergic signaling during eye development. (A) Se- rotonergic amacrine cells in Xenopus stage 42retina (red immunostaining). (B-E) Effects of 5-HT2B morpholino injection on Xenopus eye development. Lateral (B,C) views of control and injected side of the same tadpole (st. 42). The arrow in (C) points to the optic fissure that fails to close ventrally. (D,E) Hoechst nuclear staining (blue) of cryostat eye cross-sections of control and morpholino-injected stage 42tadpole: note the altered retinal layering in (E). ONL, outer nuclear layer; INL, inner nuclear layer; IPL, inner plexiform layer; GCL, ganglion cell layer; L, lens.
Fig. 5. Role of serotonergic signaling in the first branchial arch development. (A,B)
Craniofacial skeletal alterations in 5-HT2B morphants (st. 49). Alcian blue staining of a flat mount embryo showing the jaw joint region of the control (A) and injected (B) side. The jaw joint (black arrow in the control side) is lacking in the injected side; note also the reduction of the quadrate (Q) and the absence of the ventral cartilaginous muscular process of the Meckel�s cartilage, which is present in the control side (red arrow). Q, quadrate; M, Meckel�s cartilage. (C) Scheme of the role of the 5HT-2B receptor signaling in patterning the dorso-ventral axis of the first branchial arch. The scheme is based on the experimental data reported in Reisoli et al., 2010. 5-HT2B receptor signaling is both sufficient and necessary to induce and maintain Xbap (Nkx2.2) gene expression in the medial region of first branchial arch giving rise to the jaw joint, possibly cooperating with endothelin receptor signaling.
