Disruption of tph1 genes demonstrates the importance of serotonin in regulating ventilation in larval zebrafish (Danio rerio)

•Tph1a is expressed in skin and & pharyngeal arch neuroepithelial cells (NECs), and in pharyngeal arch Merkel-like cells (MLCs).•Tph1b is expressed predominately in pharyngeal arch MLCs and sporadically in skin NECs.•Knockout of tph1 resulted in similar changes of serotonergic cell density in tph1a−/−, tph1b−/− and tph1a−/−b-/- mutants.•tph1a−/− and tph1b−/− mutants showed markedly different ventilatory response when exposed to hypoxia. Serotonergic neuroepithelial cells (NECs) in larval zebrafish are believed to be O2 chemoreceptors. Serotonin (5-HT) within these NECs has been implicated as a neurotransmitter mediating the hypoxic ventilatory response (HVR). Here, we use knockout approaches to discern the role of 5-HT in regulating the HVR by targeting the rate limiting enzyme for 5-HT synthesis, tryptophan hydroxylase (Tph). Using transgenic lines, we determined that Tph1a is expressed in skin and pharyngeal arch NECs, as well as in pharyngeal arch Merkel-like cells (MLCs), whereas Tph1b is expressed predominately in MLCs. Knocking out the two tph1 paralogs resulted in similar changes in detectable serotonergic cell density between the two mutants, yet their responses to hypoxia (35 mmHg) were different. Larvae lacking Tph1a (tph1a−/− mutants) displayed a higher ventilation rate when exposed to hypoxia compared to wild-types, whereas tph1b−/− mutants exhibited a lower ventilation rate suggesting that 5-HT located in locations other than NECs, may play a dominant role in regulating the HVR.