The human visual system homeobox gene
VSX1 is a paired-like gene containing a highly conserved domain, denoted as CVC because it was originally identified in mouse
Chx10, goldfish
Vsx1 and
Caenorhabditis elegans Ceh-10 genes.
1 2 3 Although the role of this domain must be more defined, it is necessary for transcriptional regulation and efficient ubiquitination for the degradation of
Vsx1 by the 26S proteasome.
4 However, the CVC-domain of
Vsx1 is required for protein function given that mutations within the CVC domain of the
Ceh-10 gene are lethal because of defects in interneuron formation.
5 Numerous orthologs and homologs of these genes have now been isolated, and all have demonstrated a high expression level in the inner nuclear layer (INL) of developing or adult retinas, suggesting that homeobox/CVC proteins play a role in bipolar interneuron biology.
6 7 8 9 10 11 12 13 Understanding the role of such genes is a significant challenge because interneurons are thought to constitute most cells in the nervous system and relatively little is known concerning their functioning. The
Vsx1 gene was initially identified in goldfish, a species in which retinogenesis and retinal regeneration after injury is maintained throughout life, in contrast to mammals.
1 In adult goldfish retina,
Vsx1 expression is restricted to bipolar cells (BCs), suggesting that this gene stabilizes the differentiated state of these interneuron cells. However, in the immature retina,
Vsx1 is also expressed, transiently, in mitotically active cone, horizontal, and bipolar cell progenitors at the proliferative retinal margin before it is switched off in retinal cells other than BCs when differentiation begins.
1 12 Therefore, this specific BC expression results from a tightly controlled temporal and spatial downregulation of
Vsx1. This restrictive expression pattern of
Vsx1 closely parallels that of the mouse
Chx10 gene, which is indispensable for retinal progenitor cell (RPC) proliferation during the early stages of retinogenesis and for differentiation of BCs.
2 11 14 Recent results provided by the engineering of
Vsx1-null alleles in mice implicated
Vsx1 in retinal physiology.
15 16 Although these mice had normal eye appearance with typical corneal and retinal histology, retinal electrophysiological experiments indicated that
Vsx1 regulates the visual photopic pathway and that it is probably specifically required for the late differentiation of cone OFF-BC. Furthermore, among
Vsx1-BCs, some are recoverin positive whereas others are recoverin negative, suggesting heterogeneity between BCs in which
Vsx1 exerts its function.
16 Finally, several lines of evidence support the view that
Vsx1 retinal expression is downregulated in a
Vsx1-dependent manner, suggesting that
Vsx1 is required in a feedback loop to negatively regulate the generation of cone bipolar interneurons.
16