Function for Hedgehog Genes in Zebrafish Retinal Development

Abstract

The hedgehog (hh) genes encode secreted signaling proteins that have important developmental functions in vertebrates and invertebrates. In Drosophila, expression of hh coordinates retinal development by propagating a wave of photoreceptor differentiation across the eye primordium. Here we report that two vertebrate hh genes, sonic hedgehog (shh) and tiggy-winkle hedgehog (twhh), may perform similar functions in the developing zebrafish. Both shh and twhh are expressed in the embryonic zebrafish retinal pigmented epithelium (RPE), initially in a discrete ventral patch which then expands outward in advance of an expanding wave of photoreceptor recruitment in the subjacent neural retina. A gene encoding a receptor for the hedgehog protein, ptc-2, is expressed by retinal neuroepithelial cells. Injection of a cocktail of antisense (alphashh/alphatwhh) oligonucleotides reduces expression of both hh genes in the RPE and slows or arrests the progression of rod and cone photoreceptor differentiation. Zebrafish strains known to have mutations in Hh signaling pathway genes similarly exhibit retardation of photoreceptor differentiation. We propose that hedgehog genes may play a role in propagating photoreceptor differentiation across the developing eye of the zebrafish.

Positional cloning of the young mutation identifies an essential role for the Brahma chromatin remodeling complex in mediating retinal cell differentiation

“…In both invertebrate and vertebrate retinas, Ath5 is thought to regulate the expression of hedgehog genes, which in turn results in a wave of MAP kinase activity (9,27,28). Although loss-of-function studies with hedgehog genes suggest this pathway has a role in cell fate determination and patterning within the retina, the significance of MAP kinase activity in retinogenesis has not been tested (9)(10)(11)29). In situ hybridization experiments showed similar expression in yng and WT retinas for ath5 and components of the hedgehog pathway (sonic hh, tiggy-winkle hh, and the retinal receptor patched-2).…”

“…At the time of ath5 expression and cell cycle withdrawal, waves of hedgehog gene expression sweep through the retina. Hedgehog activity has been shown to regulate cell fate decisions and laminar organization (9)(10)(11)(12). After the waves of hedgehog, ath5, and cell cycle withdrawal, a wave of mitogen-activated protein (MAP) kinase activity progresses through the retina (9).…”

Neurogenesis in the Fish Retina

“…Reduced Hh signaling, such as in the syu mutant, or as accomplished through the use of antisense gene knockdown strategies or cyclopamine treatment, also results in significant attenuation of photoreceptor differentiation Stenkamp et al, 2000. The knock -down strategies applied were specifically targeted to the time when shh and twhh expression spreads throughout the RPE, leading to the conclusion that the Hh signal needed for photoreceptor differentiation likely originates in RPE cells.…”

“…Liu et al, 2001Shen and Raymond, 2004 Boucher and Hitchcock, 1998a;Mack and Fernald, 1993;Otteson et al, 2002FGFs Heisenberg et al, 1999Picker andBrand, 2005 Mack andMartinez-Morales et al, 2005Wnts Masai et al, 2005Yamaguchi et al, 2005Hh Macdonald et al, 1995Stenkamp and Frey, 2003a;Take-uchi et al, 2003Masai et al, 2005Shkumatava and Neumann, 2005;Masai et al, 2005Neumann and Nuesslein-Volhard, 2000;Shkumatava et al, 2004;Stenkamp and Frey, 2003a;Stenkamp et al, 2000RA Hyatt et al, 1992, 1996bMarsh-Armstrong et al, 1994Biehlmaier et al, 2005Hyatt et al, 1996a;Prabhudesai et al, 2005Notch Yamaguchi et al, 2005Bernardos et al, 2005Scheer et al, 2001Cadherins Babb et al, 2005Malicki et al, 2003 …”

Signal integration during development: Insights from the Drosophila eye

“…In the fish, photoreceptor differentiation initiates in the center of each prospective eye field and propagates radially outward (Neumann and Nuesslein-Volhard, 2000;Stenkamp et al, 2000;Russell, 2003). To what extent the full molecular complexity of MF initiation and propagation as described in the Drosophila retina is redeployed in the context of vertebrate photoreceptor differentiation remains to be determined.…”