The Role of Serotonin and Neurotransmitters During Craniofacial Development

Abstract

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.

Association between reported venlafaxine use in early pregnancy and birth defects, national birth defects prevention study, 1997–2007

“…It is believed that these neurotransmitters may act as morphogens, signaling molecules that have a dose-dependent function on receptive cells (Lauder, 1988;Buznikov et al, 2001). Several animal studies have provided specific evi- dence for serotonin acting as a morphogen in craniofacial and cardiac development (Moiseiwitsch and Lauder, 1995;Choi et al, 1997;Moiseiwitsch, 2000;Nebigil et al, 2000;Nebigil and Maroteaux, 2001;Cô té et al, 2007). Studies have also shown that norepinephrine influences neural crest cell formation and differentiation during embryogenesis (Zhang et al, 1997;Sieber-Blum and Ren, 2000;Ren et al, 2001;Ren et al, 2003;Hu et al, 2009).…”

Unraveling new roles for serotonin receptor 2B in development: key findings from Xenopus

“…The fact that 5-HT may play a role in mouse craniofacial morphogenesis was known from time, and malformations caused by exposure of cultured mouse embryos to selective 5-HT re-uptake inhibitors, such as fluoxetine (SSRI, Prozac) and 5-HT receptor antagonists were reported (Shuey et al, 1992;Moiseiwitsch, 2000). Craniofacial morphogenesis is a complex developmental process requiring multiple and coordinated embryological events.…”

Serotonin-containing Cells of Diffuse Endocrine System of the Uterus Endometrium in Pregnancy and Postnatal Period

“…The experimental material was divided into 8 groups of 4-16 animals each. We studied the rat uterus in pregnancy (days [12][13][14] and after delivery (days 1, 3, 4, 6, 10 and 15 postnatal).…”

“…В первичной борозде были определены участки скопления биогенных аминов, которые впоследствии были обнаружены в нервной трубке и в нервном гребне. Предполагается, что серото-нин участвует в клеточной миграции и стимулирует дифференцировку клеток [14,15].…”