Abstract
The habenular nuclei of the limbic system regulate responses, such as anxiety, to aversive stimuli in the environment. The habenulae receive inputs from the telencephalon via elaborate dendrites that form in the center of the nuclei. The kinase Ulk2 positively regulates dendritogenesis on habenular neurons, and in turn is negatively regulated by the cytoplasmic protein Kctd12. Given that the habenulae are a nexus in the aversive response circuit, we suspected that incomplete habenular dendritogenesis would have profound implications for behavior. We find that Ulk2, which interacts with Kctd12 proteins via a small proline-serine rich domain, promotes branching and elaboration of dendrites. Loss of Kctd12 results in increased branching/elaboration and decreased anxiety. We conclude that fine-tuning of habenular dendritogenesis during development is essential for appropriate behavioral responses to negative stimuli.
Highlights
Appropriate neuronal morphogenesis is essential for forming the distinct functional domains of each of the hundreds of types of neurons in the brain
Kctd12 regulates the activity of Ulk2, a serine/threonine kinase that promotes filopodial extension during neuronal process formation [22,23]
We further narrowed down the potential interaction site by subdividing the PS-1 into five equal segments, and expressing constructs containing overlapping combinations of these segments
Summary
Appropriate neuronal morphogenesis is essential for forming the distinct functional domains of each of the hundreds of types of neurons in the brain. Kctd12 proteins are found in the cytoplasm of habenular neurons, including within the dendrites [19]. Kctd12 regulates the activity of Ulk2, a serine/threonine kinase that promotes filopodial extension during neuronal process formation [22,23]. The mechanisms by which Kctd12 inhibits Ulk2 activity to modulate habenular dendritogenesis are not known.
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