RRC ID 387
Author Teraoka H, Russell C, Regan J, Chandrasekhar A, Concha ML, Yokoyama R, Higashi K, Take-Uchi M, Dong W, Hiraga T, Holder N, Wilson SW.
Title Hedgehog and Fgf signaling pathways regulate the development of tphR-expressing serotonergic raphe neurons in zebrafish embryos.
Journal J. Neurobiol.
Abstract Serotonin (5HT) plays major roles in the physiological regulation of many behavioral processes, including sleep, feeding, and mood, but the genetic mechanisms by which serotonergic neurons arise during development are poorly understood. In the present study, we have investigated the development of serotonergic neurons in the zebrafish. Neurons exhibiting 5HT-immunoreactivity (5HT-IR) are detected from 45 h postfertilization (hpf) in the ventral hindbrain raphe, the hypothalamus, pineal organ, and pretectal area. Tryptophan hydroxylases encode rate-limiting enzymes that function in the synthesis of 5HT. As part of this study, we cloned and analyzed a novel zebrafish tph gene named tphR. Unlike two other zebrafish tph genes (tphD1 and tphD2), tphR is expressed in serotonergic raphe neurons, similar to tph genes in mammalian species. tphR is also expressed in the pineal organ where it is likely to be involved in the pathway leading to synthesis of melatonin. To better understand the signaling pathways involved in the induction of the serotonergic phenotype, we analyzed tphR expression and 5HT-IR in embryos in which either Hh or Fgf signals are abrogated. Hindbrain 5HT neurons are severely reduced in mutants lacking activity of either Ace/Fgf8 or the transcription factor Noi/Pax2.1, which regulates expression of ace/fgf8, and probably other genes encoding signaling proteins. Similarly, serotonergic raphe neurons are absent in embryos lacking Hh activity confirming a conserved role for Hh signals in the induction of these cells. Conversely, over-activation of the Hh pathway increases the number of serotonergic neurons. As in mammals, our results are consistent with the transcription factors Nk2.2 and Gata3 acting downstream of Hh activity in the development of serotonergic raphe neurons. Our results show that the pathways involved in induction of hindbrain serotonergic neurons are likely to be conserved in all vertebrates and help establish the zebrafish as a model system to study this important neuronal class.
Volume 60(3)
Pages 275-88
Published 2004-9-5
DOI 10.1002/neu.20023
PMID 15281067
PMC PMC2789256
MeSH Animals Animals, Genetically Modified Base Sequence Cloning, Molecular / methods Embryo, Nonmammalian Enzyme Inhibitors / pharmacology Fertilization Fibroblast Growth Factors / physiology* Gene Expression Regulation, Developmental* Green Fluorescent Proteins Hedgehog Proteins Homeodomain Proteins / metabolism In Situ Hybridization / methods LIM-Homeodomain Proteins Luminescent Proteins / metabolism Nerve Tissue Proteins / metabolism Neurons / metabolism* Pyrroles / pharmacology Raphe Nuclei / cytology* Raphe Nuclei / embryology Rod Opsins / metabolism Sequence Alignment / methods Serotonin / metabolism Signal Transduction / physiology Time Factors Trans-Activators / genetics Trans-Activators / metabolism Trans-Activators / physiology* Transcription Factors Tryptophan Hydroxylase / genetics Tryptophan Hydroxylase / metabolism Veratrum Alkaloids / pharmacology Zebrafish / embryology Zebrafish Proteins / genetics Zebrafish Proteins / metabolism*
Times Cited 50
Zebrafish rw0