Thymulin gene therapy prevents the reduction in circulating gonadotropins induced by thymulin deficiency in mice.
Integrity of the thymus during perinatal life is necessary for a proper maturation of the pituitary-gonadal axis in mice and other mammalian species. Thus congenitally athymic (nude) female mice show significantly reduced levels of circulating gonadotropins, a fact that seems to be causally related to a number of reproductive derangements described in these mutants. Interestingly, a number of in vitro studies suggest that the thymic peptide thymulin may be involved in thymus-pituitary communication. To determine the consequences of low serum thymulin in otherwise normal animals, we induced short (8 days)- and long (33 days)-term thymulin deficiency in C57BL/6 mice by neonatally injecting (intraperitoneally) an anti-thymulin serum and assessed their circulating gonadotropin levels at puberty and thereafter. Control mice received an irrelevant antiserum. Gonadotropins were measured by radioimmunoassay and thymulin by bioassay. Both long- and short-term serum thymulin immunoneutralization resulted in a significant reduction in the serum levels of gonadotropins at 33 and 45 days of age. Subsequently, we injected (intramuscularly) an adenoviral vector harboring a synthetic DNA sequence (5'-ATGCAAGCCAAATCTCAAGGTGGATCCAACTAGTAG-3') encoding a biologically active analog of thymulin, methionine-FTS, in newborn nude mice (which are thymulin deficient) and measured circulating gonadotropin levels when the animals reached 52 days of age. It was observed that neonatal thymulin gene therapy in the athymic mice restored their serum thymulin levels and prevented the reduction in circulating gonadotropin levels that typically emerges in these mutants after puberty. Our results indicate that thymulin plays a relevant physiological role in the thymus-pituitary-gonadal axis.
Goya
Rodolfo G
RG
Instituto de Investigaciones Bioquimicas de La Plata-Histology B-Comision de Investigaciones Cientificas de la Provincia de Buenos Aires, Facultad de Medicas, Universidad Nacional de La Plata, La Plata, Argentina. rgoya@netverk.com.ar
Reggiani
Paula C
PC
Vesenbeckh
Silvan M
SM
Pléau
Jean M
JM
Sosa
Yolanda E
YE
Cónsole
Gloria M
GM
Schade
Rüdiger
R
Henklein
Peter
P
Dardenne
Mireille
M
D000256:Adenoviridae / Q000235:genetics; D000595:Amino Acid Sequence; D000818:Animals; D000831:Animals, Newborn; D001483:Base Sequence; D002478:Cells, Cultured; D005260:Female; D015316:Genetic Therapy; D006062:Gonadotropins / Q000097:blood*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D011247:Pregnancy; D013935:Thymic Factor, Circulating / Q000235:genetics* / Q000276:immunology / Q000502:physiology
D006062:Gonadotropins; D013935:Thymic Factor, Circulating