Neuron-specific TGF-beta signaling deficiency results in retinal detachment and cataracts in mice

We generated a mouse model (cKO) with a conditional deletion of TGF-beta signaling in the retinal neurons by crossing TGF-beta receptor I (TGF-beta RI) floxed mice with nestin-Cre mice. Almost all of the newborn cKO mice had retinal detachment at the retinal pigment epithelium (RPE)/photoreceptor layer junction of the neurosensory retina (NSR). The immunostaining for chondroitin-6-sulfate showed a very weak reaction in cKO mice in contrast to intense staining in the photoreceptor layer in wild-type mice. Macroscopic cataracts, in one or both eyes, were observed in 50% of the mice by 6 months of age, starting as early as the first month after birth. The cKO mouse model demonstrates that the TGF-beta signaling deficiency in retinal cells leads to decreased levels of chondroitin sulfate proteoglycan in the retinal interpho to receptor matrix. This in turn causes retinal detachment due to the loss of adhesion of the NSR to RPE. (c) 2006 Elsevier Inc. All rights reserved

Female mice are more susceptible to developing inflammatory disorders due to impaired transforming growth factor beta signaling in salivary glands

Objective. Transforming growth factor 13 (TGF)3) plays a key role in the onset and resolution of autoimmune diseases and chronic inflammation. The aim of this study was to delineate the precise function of TGF beta signaling in salivary gland inflammation. Methods. We impaired TGF beta signaling in mouse salivary glands by conditionally inactivating expression of TGF beta receptor type I (TGF beta RI), either by using mouse mammary tumor virus-Cre mice or by delivering adenoviral vector containing Cre to mouse salivary glands via retrograde infusion of the cannulated main excretory ducts of submandibular glands. Results. TGF beta RI-conditional knockout (TGF beta RI-coko) mice were born normal; however, female TGF beta RI-coko mice developed severe multifocal inflammation in salivary and mammary glands and in the heart. The inflammatory disorder affected normal growth and resulted in the death of the mice at ages 4-5 weeks. Interestingly, male TGF beta RI-coko mice did not exhibit any signs of inflammation. The female TGF beta RI-coko mice also showed an increase in Th1 proinflammatory cytokines in salivary glands and exhibited an up-regulation of peripheral T cells. In addition, these mice showed an atypical distribution of aquaporin 5 in their salivary glands, suggesting likely secretory impairment. Administration of an adenoviral vector encoding Cre recombinase into the salivary glands resulted in inflammatory foci only in the glands of female TGF beta RI-loxP-flanked (floxed) mice (TGF beta RI-f/f mice), but not in those of male and female wild-type mice or male TGF beta RI-f/f mice. Conclusion. These results suggest that female mice are uniquely more susceptible to developing inflammatory disorders due to impaired TGF beta signaling in their salivary glands