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R. Rajagopal, L. K. Dattilo, D. C. Beebe; Smad-Dependent and -Independent Aspects of Bmp Receptor Signaling During Lens Induction. Invest. Ophthalmol. Vis. Sci. 2008;49(13):1136.
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To identify the downstream signaling molecules that mediate the functions of the type I BMP receptors, Bmpr1a and Acvr1, during lens formation.
Lens placodes lacking Bmpr1a and Acvr1, Smad1 and Smad5, and Smad4 were generated by mating the respective floxed mice with LeCre transgenic mice, which express Cre recombinase in the surface ectoderm. Conditional knockout (CKO) placodes were compared to wild type (WT) littermate placodes. Pregnant females were injected with BrdU (50 mg /kg) and sacrificed one hr later. Embryos were fixed, embedded in 5% agarose for orientation and in paraffin for sectioning. Sections were labeled with antibody to BrdU, Pax6 or Sox2 or with the TUNEL assay. Agarose embedded embryos were sectioned at 100 µm and labeled with an antibody against FoxE3.
Inactivation of the BMP receptors, Bmpr1a and Acvr1, in the presumptive lens ectoderm results in failure of lens formation. The Bmpr1a; Acvr1DCKO ectoderm displayed a significant increase in cell death and a decrease in proliferation. Levels of Pax6 were unaffected in the DCKO ectoderm, whereas Sox2 levels were reduced and Foxe3 staining was undetectable. In contrast, inactivation of the downstream canonical Smad signaling molecules, the Co-Smad (Smad4) or the BMP-specific R-Smads (Smad1 and 5), did not prevent lens formation. Cell death and proliferation were unaffected in the Smad4CKO placodes. Smad1; 5DCKO placodes displayed increased cell death, but no change in proliferation. Similar to the receptor DKO, levels of Pax6 were unaffected in Smad4CKO and Smad1; 5DCKO placodes. Sox2 levels were reduced in placodes lacking the Smad proteins. Unlike the receptor knockout, Foxe3 levels were unaffected in Smad4CKO placodes.
Signaling through the type I BMP receptors, Bmpr1a and Acvr1, regulates several aspects of lens induction. Some of these functions are mediated by the canonical Smad signaling pathway (Sox2 levels), whereas others are not (lens formation, FoxE3 expression, cell proliferation). Placode cell survival is R-Smad-dependent, but Smad4-independent.
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