Abstract
Smad7 is an intracellular inhibitory protein that antagonizes the signaling of TGF-β family members. Deletion of Smad7 in the mouse leads to an abnormality in heart development. However, whether Smad7 has a functional role in the development of other organs has been elusive. Here we present evidence that Smad7 imparts a role to eye development in the mouse. Smad7 is expressed in both the lens and retina in the developing embryonic eye. Depletion of Smad7 caused various degrees of coloboma and microphthalmia with alterations in cell apoptosis and proliferation in eyes. Smad7 was implicated in lens differentiation but was not required for the induction of the lens placode. The development of the periocular mesenchyme was retarded with the down-regulation of Bmp7 and Pitx2 in mutant mice. Retinal spatial patterning was affected by Smad7 deletion and was accompanied by altered bone morphogenetic protein (BMP) signaling. At late gestation stages, TGF-β signaling was up-regulated in the differentiating retina. Smad7 mutant mice displayed an expanded optic disc with increasing of sonic hedgehog (SHH) signaling. Furthermore, loss of Smad7 led to a temporal change in retinal neurogenesis. In conclusion, our study suggests that Smad7 is essential for eye development. In addition, our data indicate that alterations in the signaling of BMP, TGF-β, and SHH likely underlie the defects in eye development caused by Smad7 deletion.
Highlights
It is unknown whether Smad7 has a functional role in eye development
Ablation of Smad7 Leads to Coloboma and Microphthalmia— To determining the potential role of Smad7 during eye development, we examined the expression of Smad7 in the developing eyes at both mRNA and protein levels (Fig. 1A)
We found that in the mutant mice, the Bmp7 transcript level was distinguishably lower in the surrounding periocular mesenchyme, indicating that the bone morphogenetic protein (BMP) signal was reduced in this region (Fig. 4, E and F)
Summary
It is unknown whether Smad has a functional role in eye development. Results: Eye development is defective in Smad null mice and is accompanied by alterations in the patterning of BMP signals, periocular mesenchymal genes, and sonic hedgehog signaling. Retinal spatial patterning was affected by Smad deletion and was accompanied by altered bone morphogenetic protein (BMP) signaling. Our data indicate that alterations in the signaling of BMP, TGF-, and SHH likely underlie the defects in eye development caused by Smad deletion. Overexpression of Smad in the epithelial cells in mice leads to abnormal eyelid closure and thin corneal stroma [32], indicating that dyregulation of Smad in the adjacent ocular tissue may cause pathological alterations in the eye formation Currently it is unknown whether Smad affects eye development. We found that deletion of Smad led to multiple defects in eye development including dysregulation of lens differentiation, alteration of periocular mesenchyme, disruption of the retina patterning, and changes in the optic stalk. We have shown that Smad is essential for the timely regulation of the distinct signaling pathways during embryonic eye development
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