149. SMAD3 DOSAGE INFLUENCES TESTICULAR MATURATION

Abstract

Activin A, a TGF-beta superfamily ligand which signals via Smad2 and Smad3, is critical for normal mouse testis development and quantitatively normal sperm production.  Whereas activin enhances immature Sertoli cell proliferation (1), excessive activin production causes Sertoli cell tumours (2); this is alleviated when mice lack Smad3 (3).  Sertoli cells exhibit developmentally regulated Smad utilization in activin signalling.  Immature Sertoli cells signal via Smad3 while the onset of Smad2-mediated signal transduction correlates with Sertoli cell maturation (4).  This change coincides with decreased testicular Smad3 production at puberty and a shift in follicle stimulating hormone (FSH)-induced Smad transcription, from Smad3 in 6 dpp (days post partum) Sertoli cells to Smad2 in 15 dpp cells.  These findings suggest that Smad3 is more important for testis development than adult spermatogenesis.  To test this hypothesis, we examined testis development in Smad3^+/– and Smad3^–/– mice.  At 7 dpp, testis weight and cord diameter were reduced in Smad3^–/–mice, indicating impaired Sertoli cell proliferation.  Levels of FSH, a potent Sertoli cell mitogen, were unaltered.  Histological analysis revealed advanced spermatogenesis in heterozygous mice, with round spermatids already present at 16 dpp.  Quantitative PCR also identified advanced Sertoli and germ cell maturation in Smad3^+/– mice, while Leydig cell maturation appeared unaltered.  Adult Smad3^+/– and Smad3^–/– mice were fertile, but had smaller testes.  This is the first study relating Smad3 levels to puberty onset and identifies the Smad3^+/– mouse as a model of peripheral precocious puberty with otherwise normal physiological status, i.e. no gonadal tumours and normal FSH levels.  These results demonstrate that FSH influences testis growth and maturation by regulating Smad3 expression and highlights the importance of testing whether environmental factors, toxicants and endocrine disruptors affect Smad3 expression, thereby leading to altered testis development.