Defining the master regulators of retinal wound-healing response is the holy grail of transcriptome-wide analyses. To predict regulatory networks, we integrated transcriptome-wide changes with genetic linkage analysis and bioinformatics. Our studies yielded three complementary insights. First, groups of functionally related genes underlie the early, delayed, and sustained responses of wound healing. For example, transcriptional factor upregulation define the early response, whereas glial reactive markers and crystallin family upregulation define the sustained response. Second, expression of a subset of neural development, proliferation, and cell survival genes displayed genetic linkage to a locus that includes positional candidate genes Id2 and Lpin1. Third, mice with a nonfunctional Lipin 1 protein displayed increased ganglion cell survival and crystallin expression after optic nerve crush. The Crystallin Network represents one of the first modulatory mechanisms predicted from expression data of injured retina, expression genetics, and bioinformatics.
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EEG received support from PHS grant RO1EY017841, NIH/NEI Core Grant 5P30 EY13080-04S1, and unrestricted grant from Research to Prevent Blindness. FVC received support from Daniel L. Gerwin Fellowship, Fight For Sight fellowships SF04031 and PD07010, International Retinal Research Foundation (Charles D. Kelman, MD Postdoctoral Scholar award), NIH Training Grant 5T32 HD07491, and Knights Templar Eye Foundation.
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