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Serotonergic agents (uptake inhibitors, receptor ligands) cause significant craniofacial malformations in cultured mouse embryos suggesting that 5-hydroxytryptamine (serotonin) (5-HT) may be an important regulator of craniofacial development. To determine whether serotonergic regulation of cell migration might underly some of these effects, cranial neural crest (NC) explants from embryonic day 9 (E9) (plug day = El) mouse embryos or dissociated mandibular mesenchyme cells (derived from NC) from E12 embryos were placed in a modified Boyden chamber to measure effects of serotonergic agents on cell migration. A dosedependent effect of 5-HT on the migration of highly motile cranial NC cells was demonstrated, such that low concentrations of 5-HT stimulated migration, whereas this effect was progressively lost as the dose of 5-HT was increased. The cranial neural crest (NC) gives rise to most of the mesenchyme (also known as ectomesenchyme) of the craniofacial region (1, 2) and contributes to the endocardial cushions of the heart (3, 4). In the mouse, NC cells start to emerge from the lateral borders of the neuroepithelium or neural folds during early stages of neurulation (5, 6). Although a passive distribution of cranial NC in the mouse has been suggested (7), there is evidence that these cells actively migrate toward the developing pharyngeal arches and frontonasal process (8). Here, they differentiate into mesenchymal derivatives, such as bone, cartilage, dentin, and dental pulp (2,3,5).A number of different signals have been implicated in stimulation and guidance of NC migration, including growth factors, extracellular matrix (ECM) molecules, and their receptors. Using the chick as an experimental model, BronnerFraser and others have investigated the involvement of several ECM molecules in NC migration, including tenascin, fibronectin, laminin, and several types of collagen, as well as integrins, which act as receptors for some of these molecules (see ref. 9 for review). From these studies it is apparent that many of these actions are mediated by ,1 integrin subunits that are expressed on the cell surface of migrating NC.Although less well studied, humoral factors may also regulate or modulate NC migration. Increasing evidence suggests that blood-borne factors, in particular neurotransmitters, may play important roles in the development of craniofacial structures and endocardial cushions of the heart. Specifically, 5-hydroxytryptamine (serotonin) (5-HT), which appears to reach the mouse embryo from maternal sources (10), has been shown to influence development of craniofacial and cardiac mesenchyme in a dose-dependent manner (11). By employing mouse whole-embryo culture (WEC) (12), Lauder and colleagues (13-15) demonstrated the transient expression of low-affinity sites for 5-HT uptake and degradation in developing craniofacial epithelia that exhibited a striking spatiotemporal correlation with key morphogenic events in this region. Recently, the 5-HT uptake transporter has been localized in developing cr...

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Several neurotransmitters, in particular serotonin (5-HT), have demonstrated multiple functions during early development and mid-gestational craniofacial morphogenesis. Early studies indicated that 5-HT is present in the oocyte, where it appears to function as a regulator of cell cleavage. Later, it has a significant role during gastrulation, during which there are significant areas of 5-HT uptake in the primitive streak. Subsequently, in association with neurulation, 5-HT uptake is seen in the floor plate of the developing neural tube. During neural crest formation and branchial arch formation, 5-HT has been demonstrated to facilitate cell migration and stimulate cell differentiation. During morphogenesis of the craniofacial structures, 5-HT stimulates dental development and may aid in cusp formation. All of the most commonly prescribed antidepressant drugs inhibit serotonin uptake, yet they do not appear to cause major craniofacial malformations in vivo. Given the wide spectrum of effects that 5-HT has during development, it is difficult to understand why these anti-depressants are not major teratogens. Redundancy within the system may allow receptor and uptake pathways to function normally even with lower than normal levels of circulating serotonin. Serotonin-binding proteins, that are expressed in most craniofacial regions at critical times during craniofacial development, may have a buffering capacity that maintains adequate 5-HT tissue concentrations over a wide range of 5-HT serum concentrations. Dental development appears to be particularly sensitive to even small fluctuations in concentrations of 5-HT. Therefore, it may be that children of patients who have received selective serotonergic re-uptake inhibitors (such as Prozac and Zoloft) or the less selective tricyclic anti-depressant drugs (such as Elavil) would be at a higher risk for developmental dental defects such as anodontia and hypodontia. In this review, the evidence supporting a role for 5-HT during mammalian craniofacial development is discussed. A series of models is proposed that may explain how the craniofacial effects of 5-HT are mediated.

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