Transforming Growth Factor α Contributes to the Mechanism by which Hypothalamic Injury Induces Precocious Puberty

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 88; no. 21; pp. 9743 - 9747
• Main Authors: Junier, Marie-Pierre, Ma, Ying Jun, Costa, Maria E., Hoffman, Gloria, Hill, Diane F.
• Format: Journal Article
• Language: English
• Published: Washington, DC National Academy of Sciences of the United States of America 01.11.1991; National Acad Sciences
• Subjects: Animals; Antisense Elements (Genetics); Astrocytes; Biological and medical sciences; Blotting, Northern; Catechols - pharmacology; Complementary DNA; Complementary RNA; epidermal growth factor; ErbB Receptors - drug effects; Female; Fundamental and applied biological sciences. Psychology; Gene Expression; hypothalamus; Hypothalamus - injuries; Hypothalamus - physiopathology; Lesions; luteinizing hormone-releasing hormone; Messenger RNA; Neuroglia; Neurons; Nitriles - pharmacology; Nucleic Acid Hybridization; Protein-Tyrosine Kinases - antagonists & inhibitors; Puberty; Puberty, Precocious - etiology; Rats; Rats, Inbred Strains; Receptors; RNA; RNA, Messenger - genetics; Sexual differentiation and maturation. Puberty. Climacterium; Transforming Growth Factor alpha - physiology; Tyrphostins; Vertebrates: reproduction; Rat; Transforming growth factor; Rodentia; Central nervous system; Gonadotropin RH; Hypothalamus; Precocious puberty; Sexual maturation; Vertebrata; Mammalia; Female; Lesion; Brain (vertebrata)
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.88.21.9743

It has long been known that lesions of the hypothalamus lead to female sexual precocity. While an increased production of luteinizing hormone-releasing hormone (LHRH), the neurohormone that controls sexual development, appears to mediate the advancement of puberty induced by these lesions, little is known about the mechanism(s) by which hypothalamic injury activates LHRH secretion. Since brain lesions result in accumulation of neurotrophic/mitogenic activities in the injured area, we tested the hypothesis that transforming growth factor α (TGF-α), a mitogenic polypeptide recently shown to stimulate LHRH release, is produced in response to hypothalamic injury and mediates the effect of the lesion on puberty. Radiofrequency lesions of the preoptic area-anterior hypothalamic area (POA-AHA) of 22-day-old female rats resulted in precocious puberty within 7 days after the operation. RNA blot hybridization revealed that lesion-induced puberty was preceded by an increase in TGF-α mRNA levels in the POA-AHA. Epidermal growth factor (EGF) mRNA was undetectable in both intact and lesioned hypothalami. TGF-α mRNA levels, quantitated by RNase protection assays, were 3.5-fold greater in lesioned animals approaching puberty than in age-matched controls. Immunohistochemical studies, utilizing single- and double-staining procedures, demonstrated the presence of TGF-α precursor-like immunoreactivity in reactive astrocytes surrounding the lesion site. Hybridization histochemistry showed increased TGF-α mRNA expression in cells of the same area, further implicating reactive astrocytes as a site of TGF-α synthesis. The actions of TGF-α are mediated by its interaction with EGF receptors. Continuous infusion of RG-50864, an inhibitor of EGF receptor kinase activity, at the site of injury prevented the advancement of puberty induced by the lesion. These results suggest that TGF-α acting via EGF-like receptors contributes to the acceleration of puberty induced by anterior hypothalamic lesions. They also indicate that activation of TGF-α gene expression in glial cells is a component of the hypothalamic response to injury.