Nuclear receptor TLX prevents retinal dystrophy and recruits the corepressor atrophin1.
During mammalian embryogenesis, precise coordination of progenitor cell proliferation and differentiation is essential for proper organ size and function. The involvement of TLX (NR2E1), an orphan nuclear receptor, has been implicated in ocular development, as Tlx-/- mice exhibit visual impairment. Using genetic and biochemical approaches, we show that TLX modulates retinal progenitor cell proliferation and cell cycle re-entry by directly regulating the expression of Pten and its target cyclin D1. Additionally, TLX finely tunes the progenitor differentiation program by modulating the phospholipase C and mitogen-activated protein kinase (MAPK) pathways and the expression of an array of cell type-specific transcriptional regulators. Consequently, Tlx-/- mice have a dramatic reduction in retina thickness and enhanced generation of S-cones, and develop severe early onset retinal dystrophy. Furthermore, TLX interacts with atrophin1 (Atn1), a corepressor that is involved in human neurodegenerative dentatorubral-pallidoluysian atrophy (DRPLA) and that is essential for development of multiple tissues. Together, these results reveal a molecular strategy by which an orphan nuclear receptor can precisely orchestrate tissue-specific proliferation and differentiation programs to prevent retinal malformation and degeneration.
Zhang
Chun-Li
CL
Howard Hughes Medical Institute, The Salk Institute for Biological Studies, La Jolla, California 92037, USA.
Zou
Yuhua
Y
Yu
Ruth T
RT
Gage
Fred H
FH
Evans
Ronald M
RM
D000818:Animals; D017209:Apoptosis; D002118:Calcium / Q000378:metabolism; D002452:Cell Count; D002453:Cell Cycle / Q000235:genetics; D002454:Cell Differentiation; D019938:Cyclin D1 / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D012160:Retina / Q000254:growth & development / Q000378:metabolism / Q000473:pathology; D017949:Retinal Cone Photoreceptor Cells / Q000378:metabolism / Q000473:pathology; D012174:Retinitis Pigmentosa / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
D009419:Nerve Tissue Proteins; C490258:Nr2e1 protein, mouse; D018160:Receptors, Cytoplasmic and Nuclear; D012097:Repressor Proteins; C095278:atrophin-1; D019938:Cyclin D1; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse; D002118:Calcium