Serotonin receptor 6 mediates defective brain development in monoamine oxidase-A deficient mouse embryos [Signal Transduction]

February 4th, 2014 by Wang, C. C., Man, G. C. W., Chu, C. Y., Borchert, A., Ugun–Klusek, A., Billett, E. E., Kuhn, H., Ufer, C.

Monoamine oxidases (MAO-A, MAO-B) are enzymes of the outer mitochondrial membrane that metabolize biogenic amines. In the adult central nervous system MAOs have important functions for neurotransmitter homeostasis. Expression of MAO isoforms has been detected in the developing embryo. However, suppression of MAO-B does not induce developmental alterations. In contrast, targeted inhibition and knockdown of MAO-A expression (E7.5-E10.5) caused structural abnormalities in the brain. Here we explored the molecular mechanisms underlying defective brain development induced by MAO-A knockdown during in vitro embryogenesis. The developmental alterations are paralleled by diminished apoptotic activity in the affected neuronal structures. Moreover, dysfunctional MAO-A expression leads to elevated levels of embryonic serotonin (5-HT), and we found that knockdown of serotonin receptor 6 (5-Htr6) expression or pharmacologic inhibition of 5-Htr6 activity rescues the MAO-A knockdown phenotype and restores apoptotic activity in the developing brain. Our data suggest that excessive 5-Htr6 activation reduces activation of caspases-3 and -9 of the intrinsic apoptotic pathway and enhances expression of anti-apoptotic proteins bcl-2 and bcl-XL. Moreover, we found that elevated 5-HT levels in MAO-A knockdown embryos coincide with an enhanced activation of extracellular signal-regulated kinase 1/2 (ER1/2) and a reduction of proliferating cell numbers. In summary, our findings suggest that excessive 5-HT in MAO-A deficient mouse embryos triggers cellular signaling cascades via 5-Htr6, which suppresses developmental apoptosis in the brain and thus, induces developmental retardations.