title: Nr2e1 regulates retinal lamination and the development of Müller glia, S-cones, and glycineric amacrine cells during retinogenesis.
abstract: BACKGROUND
  Nr2e1 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.
  
  
  RESULTS
  Here, we studied the retinas of P7 and P21 Nr2e1 (frc/frc) mice and Nr2e1 (+/+) ↔ Nr2e1 (frc/frc) chimeras. We hypothesized that Nr2e1 differentially regulates the development of various retinal cell types, and thus the cellular composition of Nr2e1 (frc/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 Nr2e1 (frc/frc) S-cones in chimeras. Furthermore, Nr2e1 (frc/frc) Müller glia were mispositioned in the retina and misexpressed the ganglion cell-specific transcription factor Brn3a. Nr2e1 (frc/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 Nr2e1 (frc/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.
  
  
  CONCLUSIONS
  Together, 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.
authors.affiliation: Centre for Molecular Medicine and Therapeutics at the Child and Family Research Institute, University of British Columbia, 950 W 28 Ave, Vancouver, V5Z 4H4, BC, Canada.|Genetics Graduate Program, University of British Columbia, Vancouver, V6T 1Z2, BC, Canada.
authors.forename: Ximena
authors.initials: X
authors.lastname: Corso-Díaz
authors.affiliation: Centre for Molecular Medicine and Therapeutics at the Child and Family Research Institute, University of British Columbia, 950 W 28 Ave, Vancouver, V5Z 4H4, BC, Canada. simpson@cmmt.ubc.ca.|Genetics Graduate Program, University of British Columbia, Vancouver, V6T 1Z2, BC, Canada. simpson@cmmt.ubc.ca.|Department of Medical Genetics, University of British Columbia, Vancouver, V6T 1Z3, BC, Canada. simpson@cmmt.ubc.ca.|Department of Psychiatry, University of British Columbia, Vancouver, V6T 2A1, BC, Canada. simpson@cmmt.ubc.ca.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Simpson
mesh_terms: D025042:Amacrine Cells / Q000166:cytology / Q000378:metabolism*; D000818:Animals; D002452:Cell Count; D002678:Chimera; D063928:Ependymoglial Cells / Q000166:cytology / Q000378:metabolism*; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005998:Glycine / Q000378:metabolism*; D049452:Green Fluorescent Proteins / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D055495:Neurogenesis; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D012160:Retina / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism*; D017949:Retinal Cone Photoreceptor Cells / Q000166:cytology / Q000378:metabolism*; D012171:Retinal Vessels / Q000166:cytology / Q000378:metabolism; D050819:Transcription Factor Brn-3A / Q000378:metabolism; D001616:beta-Galactosidase / Q000378:metabolism
chemical_list: D005904:Glial Fibrillary Acidic Protein; C490258:Nr2e1 protein, mouse; C494189:Pou4f1 protein, mouse; D018160:Receptors, Cytoplasmic and Nuclear; D050819:Transcription Factor Brn-3A; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D001616:beta-Galactosidase; D005998:Glycine