Specification of GnRH-1 neurons by antagonistic FGF and retinoic acid signaling.
A small population of neuroendocrine cells in the rostral hypothalamus and basal forebrain is the key regulator of vertebrate reproduction. They secrete gonadotropin-releasing hormone (GnRH-1), communicate with many areas of the brain and integrate multiple inputs to control gonad maturation, puberty and sexual behavior. In humans, disruption of the GnRH-1 system leads to hypogonadotropic gonadism and Kallmann syndrome. Unlike other neurons in the central nervous system, GnRH-1 neurons arise in the periphery, however their embryonic origin is controversial, and the molecular mechanisms that control their initial specification are not clear. Here, we provide evidence that in chick GnRH-1 neurons originate in the olfactory placode, where they are specified shortly after olfactory sensory neurons. FGF signaling is required and sufficient to induce GnRH-1 neurons, while retinoic acid represses their formation. Both pathways regulate and antagonize each other and our results suggest that the timing of signaling is critical for normal GnRH-1 neuron formation. While Kallmann's syndrome has generally been attributed to a failure of GnRH-1 neuron migration due to impaired FGF signaling, our findings suggest that in at least some Kallmann patients these neurons may never be specified. In addition, this study highlights the intimate embryonic relationship between GnRH-1 neurons and their targets and modulators in the adult.
Department of Craniofacial Development, King's College London, Guy's Campus, London, SE1 9RT, UK.
Virginie
V
Sabado
Perrine
P
Barraud
Clare V H
CV
Baker
Andrea
A
Streit
D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D019070:Cell Lineage / Q000502:physiology*; D002642:Chick Embryo; D005346:Fibroblast Growth Factors / Q000378:metabolism; D007987:Gonadotropin-Releasing Hormone / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D017436:Kallmann Syndrome / Q000196:embryology* / Q000378:metabolism; D018613:Microscopy, Confocal; D046569:Neuroepithelial Cells / Q000166:cytology*; D009474:Neurons / Q000166:cytology* / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D014212:Tretinoin / Q000378:metabolism
D007987:Gonadotropin-Releasing Hormone; D014212:Tretinoin; D005346:Fibroblast Growth Factors