Dyslexia-Associated Kiaa0319-Like Protein Interacts with Axon Guidance Receptor Nogo Receptor 1

Abstract

To identify the putative interacting partners for Kiaa0319-like protein. KIAA0319-like, located near the dyslexia susceptibility locus, DYX8 in chromosome 1p34.3, has been suggested as a positional candidate for developmental dyslexia due to its homology with another gene, KIAA0319 which has been strongly established as a candidate gene for developmental dyslexia. Previous research has shown that a single marker, rs7523017 (P = 0.042) has been associated with developmental dyslexia by a Canadian group. There is little functional information about this gene and protein. In this article, we put forward further evidence that support Kiaa0319-like is a candidate for this disorder. A yeast-2-hybrid screen and co-immunopreciptiation assays were performed to find protein interacting partners of KIAA0319L. A human cortex immunohistochemistry assay was performed to show the colocalization of Kiaa0319-like and its specific interacting partner in cells. Nogo Receptor 1 (NgR1), an axon guidance receptor, was identified to have physical interactions with Kiaa0319-like protein. These two proteins interact predominantly in the cytoplasmic granules of cortical neurons in the human brain cortex. Based on this data, it can be concluded that Kiaa0319-like protein interacts with Nogo Receptor 1, supporting the idea that Kiaa0319-like protein participates in axon guidance.

An assessment of gene-by-gene interactions as a tool to unfold missing heritability in dyslexia

“…Transgenic over-expression of Grin2b in the forebrain of mice and in the cortex and hippocampus of rats results in an increased activation of the NMDA receptors, with mice and rats displaying a superior performance in various tests of learning and memory (Tang et al 1999;Wang et al 2009). Moreover, functional studies revealed that DYX1C1, KIAA0319, and GRIN2B genes are likely involved in neuronal migration and axon growth (Szalkowski et al 2011(Szalkowski et al , 2012Ito et al 1997;Cull-Candy et al 2001;Kim et al 2005;Wang et al 2006;Rosen et al 2007;Akashi et al 2009;Velayos-Baeza et al 2010;Peschansky et al 2010;Currier et al 2011;Poon et al 2011), which is in turn consistent with the original neuroanatomical finding of focal architectonic dysplasias and neuronal ectopias in brains of people with DD (Galaburda and Kemper 1979;Galaburda et al 1985) as well as with the recently proposed theoretical molecular network involved in neuronal migration and neurite growth for DD (Poelmans et al 2011). In particular, signaling through the network can be initiated at the neuronal cell membrane where the KIAA0319 proteins may function as receptors for netrin-like molecules-which regulate the direction and rate of axon/neurite outgrowthand in the direct adhesion between neurons and glial fibers during neuronal migration (Poelmans et al 2011).…”

Whole-exome sequencing supports genetic heterogeneity in childhood apraxia of speech

“…KIAA0319 has a role in appropriate adhesion between migrating neurons and radial glial fibers and may also regulate growth and differentiation of dendrites in the developing brain [97-99]. The gene has four polycystic kidney disease domains with homology to the extracellular domains of the PKD protein PKD1, which are involved in cell-adhesive functions [100].…”

Embryonic disruption of the candidate dyslexia susceptibility gene homolog Kiaa0319-like results in neuronal migration disorders

“…The function of this gene has not been completely characterized, although there is evidence that KIAA0319L interacts with the axon guidance protein Nogo receptor 1 (NgR1). This finding, combined with the fact that these proteins interacted in cortical neurons in vitro , suggested that KIAA0319L may participate in axonal guidance in the cerebral cortex (Poon et al, 2011a). Subsequent work in mice found that Kiaa0319L was localized to layers 4 and 6 of cerebral cortex, but also to most of the hippocampus, the molecular layer (and occasional Purkinje cells) of the cerebellum, thalamus, and olfactory bulb (Poon et al, 2011b).…”

“…Although the specific function of KIAA0319L is unknown, it has been shown to interact with Nogo receptor 1, an axon guidance protein (Poon et al, 2011a) that is similar to ROBO1 , a CDSG on the DYX5 locus (Nopola-Hemmi et al, 2001, Hannula-Jouppi et al, 2005), which has been shown to modulate axon guidance and neuronal migration (Wong et al, 2001, Hivert et al, 2002, Gonda et al, 2012). In the mouse brain, Kiaa0319l is expressed in both astrocytes and neurons, most strongly in the olfactory bulb, hippocampus, and neocortex (Poon et al, 2011b).…”