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L. W. Reneker, M. Jarrin, M. K. Duncan; Unfolded Protein Response (UPR) in Transgenic Mouse Lenses. Invest. Ophthalmol. Vis. Sci. 2009;50(13):4373.
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The expression of mutant proteins can cause endoplasmic reticulum (ER) stress. Prolonged ER stress can induce the unfolded protein response (UPR) which ultimately leads to cell death. The purpose of this study is to test whether overexpression of a transgene in mouse lens can result in the activation of UPR.
We selected transgenic mice expressing different types of proteins which are secretory (active form of TGFβ1), cytoplasmic (Sprouty 2) and dominant negative (dn) mutants (dn-Ras and truncated FGFR1 (referred as tR1)). Expression of BiP, an endoplasmic reticulum molecular chaperon often used as a marker for UPR activation, was examined by immunohistochemistry. Apoptotic cells in the transgenic lenses were detected by TUNEL assay.
Among the transgenic mice listed above, BiP immunoreactivity was detected in the newborn tR1 (dn-FGFR) lens, but not in the age-matched wild type lenses or the transgenic lenses overexpressing an active form of TGFβ1, dn-Ras or Spry2. BiP expression was first shown in only a few (2-3) fiber cells in the tR1 lens at embryonic day 14.5 (E14.5). As the tR1 lens grew older, BiP immunoreactivity was expanded to more fiber cells, which were localized in the area between the cortical and core region of the fiber compartment. TUNEL-positive nuclei were found in the central zone of the tR1 lens at E14.5, the time before BiP expression was upregulated. Neither TUNEL-positive nor BiP upregulation was detected before birth in the fiber compartments of the other types of transgenic mice.
Overexpression of a transgene in mouse lens does not necessarily activate the UPR. In the tR1 lens, activation of UPR occurred in the fiber cells after cell death was already detected in these cells. This finding is consistent with the previous hypothesis that FGFR-signaling is essential for lens cell survival. However, activation of UPR can contribute to some of the late stage defects in the tR1 lens.
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