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Activins Are Critical Modulators of Growth and Survival

Departments of Molecular and Human Genetics (C.W.B., L.L., D.E.H.-H., M.M.M.), Pediatrics (C.W.B.), Pathology (M.M.M.), and Molecular and Cellular Biology (M.M.M.), Baylor College of Medicine, Houston, Texas 77030

Address all correspondence and requests for reprints to: Chester W. Brown, M.D., Ph.D., Assistant Professor, Departments of Molecular and Human Genetics and Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030. E-mail: cbrown{at}bcm.tmc.edu.

Activins ßA and ßB (encoded by Inhba and Inhbb genes, respectively) are related members of the TGF-ß superfamily. Previously, we generated mice with an Inhba knock-in allele (Inhba^BK) that directs the expression of activin ßB protein in the spatiotemporal pattern of activin ßA. These mice were small and had shortened life spans, both influenced by the dose of the hypomorphic Inhba^BK allele. To understand the mechanism(s) underlying these abnormalities, we now examine growth plates, liver, and kidney and analyze IGF-I, GH, and major urinary proteins. Our studies show that activins modulate the biological effects of IGF-I without substantial effects on GH, and that activin signaling deficiency also has modest effects on hepatic and renal function. To assess the relative influences of activin ßA and activin ßB, we produced mice that express activin ßB from the Inhba^BK allele, and not from its endogenous Inhbb locus. Inhba^BK/BK, Inhbb^-/- mice have failure of eyelid fusion at birth and demonstrate more severe effects on somatic growth and survival than either of the corresponding single homozygous mutants, showing that somatic growth and life span are supported by both activins ßA and ßB, although activin ßA plays a more substantial role.

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