Abstract
BackgroundNr2e1 is a nuclear receptor crucial for neural stem cell proliferation and maintenance. In the retina, lack of Nr2e1 results in premature neurogenesis, aberrant blood vessel formation and dystrophy. However, the specific role of Nr2e1 in the development of different retinal cell types and its cell-autonomous and non-cell autonomous function(s) during eye development are poorly understood.ResultsHere, we studied the retinas of P7 and P21 Nr2e1frc/frc mice and Nr2e1+/+ ↔ Nr2e1frc/frc chimeras. We hypothesized that Nr2e1 differentially regulates the development of various retinal cell types, and thus the cellular composition of Nr2e1frc/frc retinas does not simply reflect an overrepresentation of cells born early and underrepresentation of cells born later as a consequence of premature neurogenesis. In agreement with our hypothesis, lack of Nr2e1 resulted in increased numbers of glycinergic amacrine cells with no apparent increase in other amacrine sub-types, normal numbers of Müller glia, the last cell-type to be generated, and increased numbers of Nr2e1frc/frc S-cones in chimeras. Furthermore, Nr2e1frc/frc Müller glia were mispositioned in the retina and misexpressed the ganglion cell-specific transcription factor Brn3a. Nr2e1frc/frc retinas also displayed lamination defects including an ectopic neuropil forming an additional inner plexiform layer. In chimeric mice, retinal thickness was rescued by 34 % of wild-type cells and Nr2e1frc/frc dystrophy-related phenotypes were no longer evident. However, the formation of an ectopic neuropil, misexpression of Brn3a in Müller glia, and abnormal cell numbers in the inner and outer nuclear layers at P7 were not rescued by wild-type cells.ConclusionsTogether, these results show that Nr2e1, in addition to having a role in preventing premature cell cycle exit, participates in several other developmental processes during retinogenesis including neurite organization in the inner retina and development of glycinergic amacrine cells, S-cones, and Müller glia. Nr2e1 also regulates various aspects of Müller glia differentiation cell-autonomously. However, Nr2e1 does not have a cell-autonomous role in preventing retinal dystrophy. Thus, Nr2e1 regulates processes involved in neurite development and terminal retinal cell differentiation.Electronic supplementary materialThe online version of this article (doi:10.1186/s13041-015-0126-x) contains supplementary material, which is available to authorized users.
Highlights
Nr2e1 is a nuclear receptor crucial for neural stem cell proliferation and maintenance
We studied abnormal phenotypes previously reported to be present in Nr2e1 null retinas, such as reduced retinal thickness and blood vessel numbers
Expression of enhanced green fluorescent protein (EGFP) and β-galactosidase in mouse chimeras To better understand the cell-autonomous and noncell autonomous roles of Nr2e1 during retinogenesis, we made chimeric mice comprised of Nr2e1+/+ and Nr2e1frc/frc cells, referred as Wt↔frc chimeras
Summary
Nr2e1 is a nuclear receptor crucial for neural stem cell proliferation and maintenance. We hypothesized that Nr2e1 differentially regulates the development of various retinal cell types, and the cellular composition of Nr2e1frc/frc retinas does not reflect an overrepresentation of cells born early and underrepresentation of cells born later as a consequence of premature neurogenesis. Ganglion neurons are the first cells to be generated followed by amacrine, horizontal, cones, and rods during the embryonic period, and bipolar and Müller glia during the postnatal period [1]. These cell types are organized into three nuclear layers and generate two plexiform layer neuropils where most of the synapses are confined. RPCs are heterogeneous in gene expression [13] and express transcription factors and cell cycle regulators that play dual roles in controlling RPC cell cycle and fate [12, 14, 15]
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