Control of late off-center cone bipolar cell differentiation and visual signaling by the homeobox gene Vsx1

doi:10.1073/pnas.0306520101

Control of late off-center cone bipolar cell differentiation and visual signaling by the homeobox gene Vsx1

Programs in ^*Developmental Biology, ^†Genetics, and ^¶Integrative Biology, Research Institute, Hospital for Sick Children, Toronto, ON, Cananda M5G 1X8; Departments of ^§Molecular and Medical Genetics, ^∥Laboratory Medicine and Pathobiology, and ^††Pediatrics, University of Toronto, Toronto, ON, Canada M5S 1A1; ^‡Departments of Ophthalmology and Physiology and Neuroscience, New York University School of Medicine, New York, NY 10016; and ^**Retina Foundation of the Southwest, Dallas, TX 75231

Edited by Jeremy Nathans, Johns Hopkins University School of Medicine, Baltimore, MD (received for review October 8, 2003)

Abstract

Retinal bipolar cells are interneurons that transmit visual signals from photoreceptors to ganglion cells. Although the visual pathways mediated by bipolar cells have been well characterized, the genes that regulate their development and function are largely unknown. To determine the role in bipolar cell development of the homeobox gene Vsx1, whose retinal expression is restricted to a major subset of differentiating and mature cone bipolar (CB) cells, we targeted the gene in mice. Bipolar cell fate was not altered in the absence of Vsx1 function, because the pan-bipolar markers Chx10 and Ret-B1 continued to be expressed in inner nuclear layer neurons labeled by the Vsx1-targeting reporter gene, τLacZ. The specification, number, and gross morphology of the subset of on-center and off-center (OFF)-CB cells defined by τLacZ expression from the Vsx1 locus were also normal in Vsx1 ^τLacZ/Vsx1 ^τLacZ mice. However, the terminal differentiation of OFF-CB cells in the retina of Vsx1 ^τLacZ/Vsx1 ^τLacZ mice was incomplete, as demonstrated by a substantial reduction in the expression of at least four markers (recoverin, NK3R, Neto1, and CaB5) for these interneurons. These molecular abnormalities were associated with defects in retinal function and documented by electroretinography and in vitro ganglion cell recordings specific to cone visual signaling. In particular, there was a general reduction in the light-mediated activity of OFF, but not on-center, ganglion cells. Thus, Vsx1 is required for the late differentiation and function of OFF-CB cells and is associated with a heritable OFF visual pathway-specific retinal defect.

Footnotes

↵ ‡‡ To whom correspondence should be addressed. E-mail: mcinnes{at}sickkids.ca.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations: ON, on-center; OFF, off-center; CB, cone bipolar; IPL, inner plexiform layer; RB, rod bipolar; ERG, electroretinography; β-gal, β-galactosidase.