Mice and cattle with genetic deficiencies in myostatin exhibit dramatic increases in skeletal muscle mass, suggesting that myostatin normally suppresses muscle growth. Whether this increased muscling results from prenatal or postnatal lack of myostatin activity is unknown. Here we show that myostatin circulates in the blood of adult mice in a latent form that can be activated by acid treatment. Systemic overexpression of myostatin in adult mice was found to induce profound muscle and fat loss analogous to that seen in human cachexia syndromes. These data indicate that myostatin acts systemically in adult animals and may be a useful pharmacologic target in clinical settings such as cachexia, where muscle growth is desired.
Growth/differentiation factor-9 (GDF-9) is a previously described member of the transforming growth factor-beta superfamily expressed specifically in the ovary in adult mice. Using in situ hybridization methods, we have localized the expression of GDF-9 messenger RNA (mRNA) exclusively to oocytes. GDF-9 mRNA was detected in oocytes at all stages of follicular development, except in primordial follicles, in both neonatal and adult ovaries. GDF-9 mRNA continued to be expressed in oocytes after ovulation, but disappeared by 1.5 days after fertilization. Based on Western analysis of ovarian extracts using antibodies raised against recombinant GDF-9 protein, GDF-9 mRNA expressed by oocytes appears to be translated. A human homolog of GDF-9 was isolated from a complementary DNA library prepared from adult ovary mRNA. The predicted human protein is 90% identical to murine GDF-9 in the mature portion of the molecule. These results are significant because no other growth factor-like molecules have been shown to be expressed specifically by oocytes and, together with results of previous studies, suggest that ovarian development and function are regulated by factors produced by both oocytes and support cells of the ovary.
Growth/differentiation factor 11 (Gdf11) is a transforming growth factor beta family member previously shown to control anterior/posterior patterning of the axial skeleton. We now report that Gdf11 also regulates kidney organogenesis. Mice carrying a targeted deletion of Gdf11 possess a spectrum of renal abnormalities with the majority of mutant animals lacking both kidneys. Histological analysis revealed a failure in ureteric bud formation at the initial stage of metanephric development in most Gdf11 mutant embryos examined. The metanephric mesenchyme of mutant embryos lacking a ureteric bud was found to be defective in the expression of glial cell line-derived neurotrophic factor (Gdnf), a gene known to direct ureteric bud outgrowth. The addition of Gdnf protein to urogenital tracts taken from Gdf11 null embryos induced ectopic ureteric bud formation along the Wolffian duct. Our studies suggest that Gdf11 may be important in directing the initial outgrowth of the ureteric bud from the Wolffian duct by controlling the expression of Gdnf in the metanephric mesenchyme.
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