Article

Asymmetric Inhibition of Ulk2 Causes Left-Right Differences in Habenular Neuropil Formation

Department of Biological Sciences, Vanderbilt University, Nashville, Tennessee 37205, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.75). 07/2011; 31(27):9869-78. DOI: 10.1523/JNEUROSCI.0435-11.2011
Source: PubMed

ABSTRACT Studies of the zebrafish epithalamus have provided recent insights into the development of left-right brain asymmetry, which is crucial to normal human brain function. The habenular nuclei of zebrafish are robustly asymmetric, with dense elaboration of neuropil only in the left lateral subnucleus. Because this feature is tightly correlated with asymmetric expression of K(+) channel tetramerization domain-containing proteins 12.1 and 12.2 (Kctd12.1/12.2), we screened for Kctd12.1-interacting proteins to identify molecular mechanisms leading to neuropil asymmetry, and uncovered a novel interaction between Kctd12.1 and Unc-51-like kinase 2 (Ulk2). We show here that knockdown of Ulk2 or overexpression of Kctd12 proteins reduces asymmetric neuropil elaboration. Conversely, overexpression of Ulk2 or mutation of kctd12 genes causes excess neuropil elaboration. We conclude that Ulk2 activity promotes neuropil elaboration while Kctd12 proteins limit Ulk2 activity asymmetrically. This work describes a regulatory mechanism for neuronal process extension that may be conserved in other developmental contexts in addition to the epithalamus.

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    • "Accumulations of neuropil differ between the left and right dorsal habenulae of larval zebrafish, as visualized by immunolabeling with antibodies against acetylated α-Tubulin (Concha et al., 2000; Taylor et al., 2011) or Synaptic Vesicle Protein 2 (SV2) (Hendricks and Jesuthasan, 2007; Miyasaka et al., 2009), and by labeling of membrane-tagged GFP in live Tg(gng8:nfsB- CAAX-GFP) c375 larvae. The left side has an expanded neuropil that extends the width of the dorsal habenula, while the right dorsal habenula has three more distinct, small clusters (Figure 1E). "
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