ZFIN ID: ZDB-PUB-170720-18
The Central Nervous System Regulates Embryonic HSPC Production via Stress-Responsive Glucocorticoid Receptor Signaling
Kwan, W., Cortes, M., Frost, I., Esain, V., Theodore, L.N., Liu, S.Y., Budrow, N., Goessling, W., North, T.E.
Date: 2016
Source: Cell Stem Cell   19: 370-82 (Journal)
Registered Authors: Goessling, Wolfram, North, Trista
Keywords: none
MeSH Terms:
  • Animals
  • Cell Count
  • Cell Hypoxia/drug effects
  • Cell Proliferation/drug effects
  • Central Nervous System/metabolism*
  • Embryo, Nonmammalian/drug effects
  • Embryo, Nonmammalian/metabolism
  • Embryonic Stem Cells/drug effects
  • Embryonic Stem Cells/metabolism*
  • Fluoxetine/pharmacology
  • Hematopoietic Stem Cells/drug effects
  • Hematopoietic Stem Cells/metabolism*
  • Hypothalamo-Hypophyseal System/drug effects
  • Hypothalamo-Hypophyseal System/metabolism
  • Hypoxia-Inducible Factor 1, alpha Subunit/metabolism
  • Kidney/drug effects
  • Kidney/metabolism
  • Receptors, Glucocorticoid/metabolism*
  • Serotonergic Neurons/drug effects
  • Serotonergic Neurons/metabolism
  • Serotonin/pharmacology
  • Signal Transduction*/drug effects
  • Stress, Physiological/drug effects
  • Sympathetic Nervous System/drug effects
  • Sympathetic Nervous System/metabolism
  • Tryptophan Hydroxylase/metabolism
  • Zebrafish/embryology
PubMed: 27424782 Full text @ Cell Stem Cell
Hematopoietic stem and progenitor cell (HSPC) specification is regulated by numerous defined factors acting locally within the hemogenic niche; however, it is unclear whether production can adapt to fluctuating systemic needs. Here we show that the CNS controls embryonic HSPC numbers via the hypothalamic-pituitary-adrenal/interrenal (HPA/I) stress response axis. Exposure to serotonin or the reuptake inhibitor fluoxetine increased runx1 expression and Flk1(+)/cMyb(+) HSPCs independent of peripheral innervation. Inhibition of neuronal, but not peripheral, tryptophan hydroxlyase (Tph) persistently reduced HSPC number. Consistent with central HPA/I axis induction and glucocorticoid receptor (GR) activation, GR agonists enhanced, whereas GR loss diminished, HSPC formation. Significantly, developmental hypoxia, as indicated by Hif1α function, induced the HPA/I axis and cortisol production. Furthermore, Hif1α-stimulated HSPC enhancement was attenuated by neuronal tph or GR loss. Our data establish that embryonic HSC production responds to physiologic stress via CNS-derived serotonin synthesis and central feedback regulation to control HSC numbers.