Nuclear receptor TLX prevents retinal dystrophy and recruits the corepressor atrophin1

Chun Li Zhang, Yuhua Zou, Ruth T. Yu, Fred H. Gage, Ronald M. Evans

Research output: Contribution to journalArticle

87 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1308-1320
Number of pages13
JournalGenes and Development
Volume20
Issue number10
DOIs
StatePublished - May 15 2006

Fingerprint

Retinal Dystrophies
Orphan Nuclear Receptors
Co-Repressor Proteins
Cytoplasmic and Nuclear Receptors
Stem Cells
Progressive Myoclonic Epilepsy
Cell Proliferation
Retinal Degeneration
Organ Size
Cyclin D1
Vision Disorders
Type C Phospholipases
Mitogen-Activated Protein Kinases
Embryonic Development
Retina
Molecular Biology
Cell Differentiation
Cell Cycle
Early Onset Severe Retinal Dystrophy

Keywords

  • Atrophin
  • Neurodegeneration
  • Nuclear receptor
  • PTEN
  • Retinal dystrophy
  • TLX

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

Cite this

Nuclear receptor TLX prevents retinal dystrophy and recruits the corepressor atrophin1. / Zhang, Chun Li; Zou, Yuhua; Yu, Ruth T.; Gage, Fred H.; Evans, Ronald M.

In: Genes and Development, Vol. 20, No. 10, 15.05.2006, p. 1308-1320.

Research output: Contribution to journalArticle

Zhang, Chun Li ; Zou, Yuhua ; Yu, Ruth T. ; Gage, Fred H. ; Evans, Ronald M. / Nuclear receptor TLX prevents retinal dystrophy and recruits the corepressor atrophin1. In: Genes and Development. 2006 ; Vol. 20, No. 10. pp. 1308-1320.
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