NEUROSCIENCE Wnt Gets Dendrites Right

Proper function of the nervous system requires that neurons make appropriate contacts with other neurons through their dendritic arbors, and defects in dendritic structures are associated with mental retardation in humans. Neuronal activity is required for correct outgrowth and branching of dendrites. Recent evidence has shown that wingless or Wnt signaling, which is so important in regulating other aspects of development, is also a crucial regulator of dendritic development. Wayman et al. present a series of experiments that piece together a calcium-dependent signaling pathway that appears to link neuronal activity with transcriptional control of Wnt expression. In cultured rat hippocampal neurons, the authors used siRNA to restrict expression of the isoform of calcium/calmodulin-dependent protein kinase I (CaMKI) and show that this isoform is specifically required for activity-dependent development of dendrites through its activation of the mitogen-activated protein kinase ERK (extracellular signal-regulated kinase). Furthermore, constitutively active forms of MEK (a protein kinase that acts in the kinase cascade that activates ERK) or CaMKI could replace neuronal activation in stimulating dendrite development. The transcription factor CREB (cyclic AMP response element-binding protein) was confirmed to be activated by this calcium-dependent activation of ERK. A serial analysis of chromatin occupancy (SACO) screen [which combines chromatin immunoprecipitation (ChIP) with a modification of SAGE (serial analysis of gene expression)] was used to identify Wnt-2 as a target of CREB activated in response to neuronal activity. Neuronal activity also stimulated transcription of Wnt-2 in cultured hippocampal slices, and expression of the Wnt antagonist Wif blocked activity-dependent dendritic outgrowth. Together the results of Wayman et al. show a pathway from the NMDA (N-methyl-D-aspartate) receptor transmitted through CaMK kinase, CamKI, the GTPase Ras, ERK, and CREB that leads to transcriptional control of Wnt. It is possible, the authors propose, that a similar pathway could control Wnt signaling in other developmental contexts.

G. A. Wayman, S. Impey, D. Marks, T. Saneyoshi, W. F. Grant, V. Derkach, T. R. Soderling, Activity-dependent dendritic arborization mediated by CaM-kinase I activation and enhanced CREB-dependent transcription of Wnt-2. Neuron 50, 897-909 (2006). [Online Journal]