Ocular retardation mouse caused by Chx10 homeobox null allele: impaired retinal progenitor proliferation and bipolar cell differentiation

Abstract

Ocular retardation (or) is a murine eye mutation causing microphthalmia, a thin hypocellular retina and optic nerve aplasia. Here we show that mice carrying the OrJ allele have a premature stop codon in the homeobox of the Chx10 gene, a gene expressed at high levels in uncommitted retinal progenitor cells and mature bipolar cells. No CHX10 protein was detectable in the retinal neuroepithelium of orJ homozygotes. The loss of CHX10 leads both to reduced proliferation of retinal progenitors and to a specific absence of differentiated bipolar cells. Other major retinal cell types were present and correctly positioned in the mutant retina, although rod outer segments were short and retinal lamination was incomplete. These results indicate that Chx10 is an essential component in the network of genes required for the development of the mammalian eye, with profound effects on retinal progenitor proliferation and bipolar cell specification or differentiation. off

Analysis of opo cis-regulatory landscape uncovers Vsx2 requirement in early eye morphogenesis

“…In contrast to our observations, no optic cup morphogenetic defects have been reported in Vsx2-mutant mice (or J ), despite the range of variability described for this classical mutation 13,61 . A couple of alternative explanations may account for this discrepancy.…”

“…In agreement with our observations (Fig. 6F and Supplementary Table 6), microphthalmia has already been described in vsx2 loss-of-function models in both mouse and zebrafish 13,16 . Moreover, at optic cup stages, morphant retinas showed reduced cell number without exhibiting increased cell death (that is, pyknotic nuclei) or significant variation of the mitotic index ( Supplementary Fig.…”

“…This TF was initially identified in mutant mice and human patients as an important regulator of retinal precursors' proliferation and lineage specification 13,14 . Later studies in mice found that Vsx2 played an essential role in the specification of the neural retina domain, mainly by repressing Mitf family members Mitf and Tfec, and hence preventing the activation of the RPE genetic programme 17,18,20 .…”

“…Initial analysis of Vsx2 function described that its mutation in mice (ocular retardation, or j ) resulted in microphthalmia, and revealed its essential role in neuroepithelial proliferation and bipolar cells differentiation 13 . Similar phenotypes were also observed in human Vsx2 mutations 14 and in vsx2-depleted embryos in zebrafish 15,16 .…”

Rb regulates proliferation and rod photoreceptor development in the mouse retina

“…The overall size of the retina and the proportion of each cell type contained therein is essential for proper visual processing; therefore, during retinal development, cell cycle exit and cell fate specification are coordinated to ensure that the adult retina forms appropriately 1,2 . When cell proliferation and cell fate specification become uncoupled, as in retinoblastoma 3 , microphthalmia 4,5 and some forms of retinal dysplasia 6,7 and degeneration 8 , vision is severely compromised. By studying individual proteins that integrate the decision to exit the cell cycle and to specify cell fate, we may begin to gain insights into the synchronization of these two important processes during neural development.…”