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

Abstract

SUMMARY 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 (Hb) 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 reduce asymmetric neuropil elaboration. Conversely, overexpression of Ulk2 or mutation of kctd12 genes cause 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.

Opposite Effects of KCTD Subunit Domains on GABAB Receptor-mediated Desensitization

“…Analysis of the human and zebrafish KCTD proteins revealed that they are distinct from voltage-gated K ϩ channels, due to differences in their T1 domains and the absence of transmembrane domains (17,26,27). Our phylogenetic analysis based on the amino acid alignment of the T1 domains of all annotated human KCTD proteins and their orthologues revealed that they diverged deeply in time, preceding the split of animals from plants.…”

Asymmetry of the Brain: Development and Implications

“…Various asymmetrically expressed factors, such as Kctd12.1, Kctd12.2, and Daam1a (dishevel associated activator of morphogenesis), have been associated with the growth of habenular neuropils while not apparently being required for the specification of habenular neuronal subtypes (30,157) (Table 1). In addition to dendritic extensions from habenular neurons, these neuropil domains contain afferent connections from pp cells to the left habenula (33) and from a subset of mitral cells of the olfactory bulb to the right habenula (74,116).…”

Expression of a novel serine/threonine kinase gene, Ulk4, in neural progenitors during Xenopus laevis forebrain development

“…These proteins are known to be involved in different biological processes. For example, Ulk1 and Ulk2 are major regulators of autophagy (Ro et al, 2013); Ulk2 is reported to be involved in the development of some brain areas such as the habenula (Taylor et al, 2011); Ulk3 is involved in the regulation of the Sonic hedgehog signaling pathway (Maloverjan et al, 2010) that plays a crucial role in brain development (Fuccillo et al, 2006); moreover, deficiency of Stk36 or Ulk4 leads to a hydrocephalus-like phenotype (Merchant et al, 2005;Vogel et al, 2012). These data suggest that Ulk4 family members could be critical for the development and function of the nervous system.…”