Leucine-rich repeat kinase 2 modulates retinoic acid-induced neuronal differentiation of murine embryonic stem cells

PLoS One. 2011;6(6):e20820. doi: 10.1371/journal.pone.0020820. Epub 2011 Jun 9.

Abstract

Background: Dominant mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most prevalent cause of Parkinson's disease, however, little is known about the biological function of LRRK2 protein. LRRK2 is expressed in neural precursor cells suggesting a role in neurodevelopment.

Methodology/principal findings: In the present study, differential gene expression profiling revealed a faster silencing of pluripotency-associated genes, like Nanog, Oct4, and Lin28, during retinoic acid-induced neuronal differentiation of LRRK2-deficient mouse embryonic stem cells compared to wildtype cultures. By contrast, expression of neurotransmitter receptors and neurotransmitter release was increased in LRRK2+/- cultures indicating that LRRK2 promotes neuronal differentiation. Consistently, the number of neural progenitor cells was higher in the hippocampal dentate gyrus of adult LRRK2-deficient mice. Alterations in phosphorylation of the putative LRRK2 substrates, translation initiation factor 4E binding protein 1 and moesin, do not appear to be involved in altered differentiation, rather there is indirect evidence that a regulatory signaling network comprising retinoic acid receptors, let-7 miRNA and downstream target genes/mRNAs may be affected in LRRK2-deficient stem cells in culture.

Conclusion/significance: Parkinson's disease-linked LRRK2 mutations that associated with enhanced kinase activity may affect retinoic acid receptor signaling during neurodevelopment and/or neuronal maintenance as has been shown in other mouse models of chronic neurodegenerative diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Animals
  • Blotting, Western
  • Carrier Proteins / metabolism
  • Cell Cycle Proteins
  • Cell Differentiation / drug effects*
  • Cell Extracts
  • Cell Shape / drug effects
  • Embryonic Stem Cells / cytology*
  • Embryonic Stem Cells / drug effects
  • Embryonic Stem Cells / enzymology*
  • Eukaryotic Initiation Factors
  • Gene Expression Regulation / drug effects
  • Hippocampus / drug effects
  • Hippocampus / metabolism
  • Homeodomain Proteins / metabolism
  • Immunohistochemistry
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • Mice
  • Mice, Inbred C57BL
  • Nanog Homeobox Protein
  • Neurogenesis / drug effects
  • Neurons / cytology*
  • Neurotransmitter Agents / metabolism
  • Oligonucleotide Array Sequence Analysis
  • Phosphoproteins / metabolism
  • Phosphorylation / drug effects
  • Protein-Serine-Threonine Kinases / deficiency
  • Protein-Serine-Threonine Kinases / metabolism*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptors, Retinoic Acid / metabolism
  • Signal Transduction / drug effects
  • Substrate Specificity / drug effects
  • Tretinoin / pharmacology*

Substances

  • Adaptor Proteins, Signal Transducing
  • Carrier Proteins
  • Cell Cycle Proteins
  • Cell Extracts
  • Eif4ebp1 protein, mouse
  • Eukaryotic Initiation Factors
  • Homeodomain Proteins
  • Nanog Homeobox Protein
  • Nanog protein, mouse
  • Neurotransmitter Agents
  • Phosphoproteins
  • RNA, Messenger
  • Receptors, Retinoic Acid
  • Tretinoin
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • Lrrk2 protein, mouse
  • Protein-Serine-Threonine Kinases