Modulation of neuritogenesis by a protein implicated in X-linked mental retardation

J Neurosci. 2009 Oct 7;29(40):12419-27. doi: 10.1523/JNEUROSCI.5954-08.2009.

Abstract

Posttranscriptional regulation is an important control mechanism governing gene expression in neurons. We recently demonstrated that VCX-A, a protein implicated in X-linked mental retardation, is an RNA-binding protein that specifically binds the 5' end of capped mRNAs to prevent their decapping and decay. Previously, expression of VCX-A was reported to be testes restricted. Consistent with a role in cognitive function, we demonstrate that VCX-A is ubiquitously expressed in human tissues including the brain. Moreover, retinoic acid-induced differentiation of human SH-SY5Y neuroblastoma cells promoted the accumulation of VCX-A in distinct cytoplasmic foci within neurites that colocalize with staufen1-containing RNA granules, suggesting a role in translational suppression and/or mRNA transport. Exogenous expression of VCX-A in rat primary hippocampal neurons, which normally do not express the primate-restricted VCX proteins, promoted neurite arborization, and shRNA-directed knockdown of the VCX genes in SH-SY5Y cells resulted in a reduction of both primary and secondary neurite projections upon differentiation. We propose that the cap-binding property of VCX-A reflects a role of this protein in mRNA translational regulation. In support of this hypothesized role, we demonstrate that VCX-A can specifically bind a subset of mRNAs involved in neuritogenesis and is also capable of promoting translational silencing. Thus, VCX-A contains the capacity to modulate the stability and translation of a subset of target mRNAs involved in neuronal differentiation and arborization. It is plausible that defects of these functions in the absence of the VCX genes could contribute to a mental retardation phenotype.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Body Patterning
  • Cell Differentiation
  • Cell Line
  • Cells, Cultured
  • Gene Expression Regulation
  • Gene Silencing
  • Humans
  • Mental Retardation, X-Linked / genetics*
  • Mice
  • Neurites / physiology*
  • Neurons / cytology
  • Neurons / metabolism
  • Nuclear Proteins / metabolism*
  • Protein Biosynthesis / physiology
  • RNA / metabolism

Substances

  • Nuclear Proteins
  • VCX protein, human
  • RNA