Contributions by members of the TGFbeta superfamily to lens development
Published: 1 November 2004
David Beebe*,1, 2, Claudia Garcia1, Xiaohui Wang1, Ramya Rajagopal1, Mary Feldmeier1, Ji-Young Kim1, Anna Chytil3, Harold Moses3, Ruth Ashery-Padan4, and Michael Rauchman5
1 Dept. Ophthalmology and Visual Sciences, 2 Dept. Cell Biology and Physiology, Washington University, St. Louis, MO, USA, 3 Dept. Cancer Biology, Vanderbilt University, Nashville, TN, USA, 4 Dept. Human Genetics and Molecular Medicine, Tel-Aviv University, Ramat Aviv, Israel and 5 Dept. Biochemistry, St. Louis University, St. Louis, MO, USA
Members of the TGFbeta superfamily of growth and differentiation factors, including the TGFbeta, BMP, activin and nodal families, play important signaling roles throughout development. This paper summarizes some of the functions of these ligands in lens development. Targeted deletion of the genes encoding one of the BMP receptors, Alk3 (BMP receptor-1A), showed that signaling through this receptor is essential for normal lens development. Lenses lacking Alk3 were smaller than normal, with thin epithelial layers. The fiber cells of Alk3 null lenses became vacuolated and degenerated within the first week after birth. Lenses lacking Alk3 function were surrounded by abnormal mesenchymal cells, suggesting that the lenses provided inappropriate signals to surrounding tissues. Lens epithelial and fiber cells contained endosomes that were associated with activated (phosphorylated) SMAD1 and SMAD2. Endosomal localization of pSMAD1 was reduced in the absence of Alk3 signaling. The presence of pSMAD2 in lens fiber cell nuclei and the observation that the activin antagonist follistatin inhibited lens cell elongation suggested that an activin-like molecule participates in lens fiber cell differentiation. Lenses deficient in type II TGFbeta receptors were clear and had fiber cells of normal morphology. This suggests that TGFbeta signaling is not essential for the normal differentiation of lens fiber cells. The targeted deletion of single or multiple receptors of the TGFbeta superfamily in the lens should further characterize the role of these signaling molecules in lens development. This approach may also provide a useful way to define the downstream pathways that are activated by these receptors during the development of the lens and other tissues.
lens, TGFbeta superfamily, bone morphogenetic proteins, endosomes, differentiation