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Global Analysis of Smad2/3-Dependent TGF- Signaling in Living Mice Reveals Prominent Tissue-Specific Responses to Injury¹

Amy H. Lin^2,*, Jian Luo^2,*, Lauren H. Mondshein^*, Peter ten Dijke, Denis Vivien, Christopher H. Contag and Tony Wyss-Coray^3,*,¶

^* Department of Neurology and Neurological Sciences and Division of Neonatal and Developmental Medicine, Departments of Pediatrics, Microbiology and Immunology, and Radiology, Stanford University School of Medicine, Stanford, CA 94305; Division of Cellular Biochemistry, The Netherlands Cancer Institute, Amsterdam, The Netherlands; Institut National de la Santé et de la Recherche Médicale-Avenir, Université de Caen, GIP Cyceron, Caen, France; and ^¶ Geriatric Research Education and Clinical Center, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA 94304

Smad2 and Smad3 (Smad2/3) proteins are key signaling molecules for TGF- and some related family members regulating the transcription of several hundred genes. TGF- have key roles in development, tissue homeostasis, and the pathogenesis of many human diseases, including cancer, fibrotic disorders, developmental defects, and neurodegeneration. To study the temporal and spatial patterns of Smad2/3-dependent signaling in normal and pathological conditions in the living organism, we engineered transgenic mice with a Smad-responsive luciferase reporter construct (SBE-luc mice). Using bioluminescent imaging, we assessed Smad2/3 signaling activity noninvasively in living mice. At baseline, this activity was highest in brain, intestine, heart, and skin, and correlated with biochemical measurements of reporter activity. Primary astrocytes cultured from SBE-luc mice showed specific activation of the reporter in response to Smad2/3-activating TGF- family members. Treatment of mice with the endotoxin LPS resulted in a fast and vigorous, but transient activation of the reporter in the intestine. Although the response was similarly rapid in brain, it remained increased, indicating important but different cellular responses to endotoxin challenge in these organs. Traumatic brain injury with a needle stab resulted in local activation of Smad2/3-dependent genes and a severalfold increase in bioluminescence in living mice. SBE-luc mice can therefore be used to study temporal, tissue-specific activation of Smad2/3-dependent signaling in living mice in normal or pathological conditions as well as for the identification of endogenous or synthetic modulators of this pathway.

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