Open AccessTargeting transforming growth factor α expression to discrete loci of the neuroendocrine brain induces female sexual precocity
Author(s) -
Florence Rage,
Douglas Hill,
Miguel SenaEsteves,
Xandra O. Breakefield,
Robert J. Coffey,
Maria E. Costa,
Samuel M. McCann,
Sergio R. Ojeda
Publication year - 1997
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.94.6.2735
Subject(s) - endocrinology , medicine , biology , precocious puberty , hypothalamus , transforming growth factor , transfection , signal transduction , transforming growth factor beta , hormone , gene , microbiology and biotechnology , genetics
Precocious puberty of cerebral origin is a poorly understood disorder of human sexual development, brought about by the premature activation of those neurons that produce luteinizing hormone-releasing hormone (LHRH), the neuropeptide controlling sexual maturation. An increased production of transforming growth factor α (TGFα) in the hypothalamus has been implicated in the mechanism underlying both normal and precocious puberty. We have now used two gene delivery systems to target TGFα overexpression near LHRH neurons in immature female rats. Fibroblasts infected with a retroviral construct in which expression of the human TGFα gene is constitutively driven by the phosphoglycerate kinase promoter, or transfected with a plasmid in which TGFα expression is controlled by an inducible metallothionein promoter, were transplanted into several regions of the hypothalamus. When the cells were in contact with LHRH nerve terminals or in the vicinity of LHRH perikarya, sexual maturation was accelerated. These results suggest that precocious puberty of cerebral origin may result from a focal disorder of TGFα production within the confines of the LHRH neuron microenvironment.