Complementary Gli activity mediates early patterning of the mouse visual system

Abstract

The Sonic hedgehog (Shh) signaling pathway plays a key role in the development of the vertebrate central nervous system, including the eye. This pathway is mediated by the Gli transcription factors (Gli1, Gli2, and Gli3) that differentially activate and repress the expression of specific downstream target genes. In this study, we investigated the roles of the three vertebrate Glis in mediating midline Shh signaling in early ocular development. We examined the ocular phenotypes of Shh and Gli combination mutant mouse embryos and monitored proximodistal and dorsoventral patterning by the expression of specific eye development regulatory genes using in situ hybridization. We show that midline Shh signaling relieves the repressor activity of Gli3 adjacent to the midline and then promotes eye pattern formation through the nonredundant activities of all three Gli proteins. Gli3, in particular, is required to specify the dorsal optic stalk and to define the boundary between the optic stalk and the optic cup. Developmental Dynamics 235: 594 -605, 2006.

Suppressor of Fused Is Required to Maintain the Multipotency of Neural Progenitor Cells in the Retina

“…However, we observed no difference in the phenotypes of Sufu CKO;Gli3 ϩ/Ϫ retinae compared with Sufu CKO retinae (Cwinn and Wallace, unpublished observations). Additionally, the RPCs of Gli3 Ϫ/Ϫ mice, which also exhibit a Hh gain-of-function, presumably due to a loss of Gli3-repressor activity (Wang et al, 2000), express Pax6 and Vsx2 (Furimsky and Wallace, 2006), indicating that Gli3 repressor is not required to maintain RPC identity. Although the partial rescue in Sufu CKO;Gli2 Ϫ/Ϫ retinae could be due to an increase in Gli3 activator (Jia et al, 2009) or compensation by Gli1 (Kogerman et al, 1999;Taylor et al, 2002;Barnfield et al, 2005), our data strongly suggest that Gli2 is the principal mediator of Hh signaling in the absence of Sufu in RPCs.…”

“…2 E, available at www.jneurosci.org as supplemental material), the proneural gene, Math5 (supplemental Fig. 2, available at www.jneurosci.org as supplemental material), or Pax6 and Vsx2 (Furimsky and Wallace, 2006). Remarkably, removal of Gli2 in Sufu CKO retinae restored RPC multipotentiality based on the upregulation of Pax6 and Rax expression in double KO retinae compared with Sufu CKO retinae (Fig.…”

“…Therefore, at early stages in retinal development, Hh activation is suppressed in RPCs that are located peripheral to the wave of GC differentiation. Although the expression patterns of Gli1 and Gli2 in the developing retina have been characterized (Wang et al, 2005;Furimsky and Wallace, 2006), we sought to compare the expression domains of these Hh pathway components with the pattern of Sufu expression. At E11.5, a stage before the development of Shh-expressing ganglion cells (Wang et al, 2005), the expression of Gli1, which is a Hh target gene (Lee et al, 1997), is undetectable in the retina (Fig.…”

Emergence of dorsal-ventral polarity in ESC-derived retinal tissue

“…Previously, in a study of the optic cup of Smoothened (Smo, a mediator of Shh signaling) conditional knockout mice, Vax2 expression was found to be downregulated (Zhao et al, 2010). However, in the optic cup of Gli (a transcription factor in the Shh pathway) mutant mice, Vax2 expression was not changed (Furimsky and Wallace, 2006). Further elucidation of the roles of Shh signaling in D-V polarization is required.…”

Compartmentalization of Vertebrate Optic Neuroephithelium: External Cues and Transcription Factors

“…Indeed, genetic elimination of Shh in mice and chemical inhibition of Hh signaling in Xenopus embryos impairs vOS development, resulting in proximal-distal patterning defects (Chiang et al, 1996;Perron et al, 2003). The defective vOS development of Shh-deficient mice can be partially rescued by concomitant loss of the Gli3 (GLI family zinc finger 3) allele, suggesting that the transcriptional regulation of Hh target genes is critical for vOS development (Furimsky and Wallace, 2006;Kim and Lemke, 2006). Supporting this hypothesis, the expression of genes important for vOS development, such as Pax2 (paired box gene 2) and ventral anterior homeobox 1 (Vax1), is induced by Shh, whereas retinal determining genes, such as Pax6 and Rx/Rax (retina and anterior neural fold homeobox), are repressed by ectopically expressed Shh (Perron et al, 2003).…”