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M. Furimsky, V.A. Wallace; Complementary Gli transcription factor activity is required to mediate Sonic hedgehog signaling during murine ocular development. . Invest. Ophthalmol. Vis. Sci. 2004;45(13):3541.
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Purpose: Sonic hedgehog (Shh) is a secreted morphogen involved in patterning the central nervous system, including the eye. During ocular development, Shh from the ventral forebrain (midline) is necessary for the formation of bilaterally symmetrical optic vesicles and is later released from the retinal ganglion cells to promote retinal organization. The Shh signaling pathway is mediated by the Gli transcription factors (Gli1, Gli2 and Gli3) that control target gene expression through activating or repressive mechanisms. Gli2 and Gli3 are the primary mediators of the pathway, with Gli2 being a strong activator and Gli3 a strong repressor of target genes. Gli1 is solely an activator whose activity is controlled at the transcriptional level. The purpose of this study was to determine the unique and complementary roles of the three vertebrate Glis during early ocular development. Methods: We examined the morphological phenotypes in the developing eyes of mice with Shh and Gli mutations and monitored the expression of genes involved in early eye development (Pax6, Pax2, Vax1, Vax2 and Tbx5) using in situ hybridization. Results:The cyclopic Shh–– mutant phenotype was partially rescued in Shh––Gli3+– mutant mice as evidenced by the formation of two normal, but unseparated, optic cups with appropriate dorsal–ventral polarities. Shh––Gli3–– double knockout mice formed two partially separated rudimentary eyes with a malformed optic stalk and decreased expression of the Pax2 and Vax1 genes that are normally expressed in the stalk. Gli3–– mutant mice showed patterning defects that included the absence of optic cup/optic stalk definition (i.e. Pax6/Pax2 expression domains) and coloboma. Gli2+–Gli3–– mice displayed a phenotype similar to that of Gli3–– mice, but with exaggerated optic cup formation at the expense of optic stalk. Gli1–– and Gli2–– knockout mice did not show any individual patterning defects, but Gli1––Gli2–– double knockout mice displayed ventral optic vesicle mispatterning. Conclusions:Sonic hedgehog derived from the ventral forebrain is necessary to overcome the repressor activity of Gli3 at the midline to form bilaterally symmetrical eyes. Gli3 activity is required for the normal formation of the optic cup and the optic stalk, with Gli2 playing an important complementary role. Though Gli3 appears to play a principal role, the presence of Gli1 or Gli2 is necessary for appropriate early ocular development in the mouse.
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