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Valproic acid-inducible Arl4D and cytohesin-2/ARNO, acting through the downstream Arf6, regulate neurite outgrowth in N1E-115 cells. | LitMetric

AI Article Synopsis

  • Valproic acid (VPA) enhances neuronal differentiation and processes such as neurite outgrowth, although the exact molecular mechanisms are not well understood.
  • The study reveals that VPA increases the expression of cytohesin-2, a guanine-nucleotide exchange factor involved in neurite outgrowth regulation, and that inhibiting cytohesin-2 or knocking down related proteins affects this process.
  • It identifies Arl4D, a small GTPase, as a key regulator in this pathway, confirming that both cytohesin-2 and Arf6 play essential roles in mediating neurite formation influenced by VPA.

Article Abstract

The mood-stabilizing agent valproic acid (VPA) potently promotes neuronal differentiation. As yet, however, little is known about the underlying molecular mechanism. Here, we show that VPA upregulates cytohesin-2 and mediates neurite outgrowth in N1E-115 neuroblastoma cells. Cytohesin-2 is the guanine-nucleotide exchange factor (GEF) for small GTPases of the Arf family; it regulates many aspects of cellular functions including morphological changes. Treatment with the specific cytohesin family inhibitor SecinH3 or knockdown of cytohesin-2 with its siRNA results in blunted induction of neurite outgrowth in N1E-115 cells. The outgrowth is specifically inhibited by siRNA knockdown of Arf6, but not by that of Arf1. Furthermore, VPA upregulates Arl4D, an Arf-like small GTPase that has recently been identified as the regulator that binds to cytohesin-2. Arl4D knockdown displays an inhibitory effect on neurite outgrowth resulting from VPA, while expression of constitutively active Arl4D induces outgrowth. We also demonstrate that the addition of cell-permeable peptide, coupling the cytohesin-2-binding region of Arl4D into cells, reduces the effect of VPA. Thus, Arl4D is a previously unknown regulator of neurite formation through cytohesin-2 and Arf6, providing another example that the functional interaction of two different small GTPases controls an important cellular function.

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Source
http://dx.doi.org/10.1016/j.yexcr.2009.03.012DOI Listing

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