Normal radial migration and lamination are maintained in dyslexia-susceptibility candidate gene homolog Kiaa0319 knockout mice

Abstract

Developmental dyslexia is a common disorder with a strong genetic component, but the underlying molecular mechanisms are still unknown. Several candidate dyslexia-susceptibility genes, including KIAA0319, DYX1C1, and DCDC2, have been identified in humans. RNA interference experiments targeting these genes in rat embryos have shown impairments in neuronal migration, suggesting that defects in radial cortical migration could be involved in the disease mechanism of dyslexia. Here we present the first characterisation of a Kiaa0319 knockout mouse line. Animals lacking KIAA0319 protein do not show anatomical abnormalities in any of the layered structures of the brain. Neurogenesis and radial migration of cortical projection neurons are not altered, and the intrinsic electrophysiological properties of Kiaa0319-deficient neurons do not differ from those of wild-type neurons. Kiaa0319 overexpression in cortex delays radial migration, but does not affect final neuronal position. However, knockout animals show subtle differences suggesting possible alterations in anxiety-related behaviour and in sensorimotor gating. Our results do not reveal a migration disorder in the mouse model, adding to the body of evidence available for Dcdc2 and Dyx1c1 that, unlike in the rat in utero knockdown models, the dyslexia-susceptibility candidate mouse homolog genes do not play an evident role in neuronal migration. However, KIAA0319 protein expression seems to be restricted to the brain, not only in early developmental stages but also in adult mice, indicative of a role of this protein in brain function. The constitutive and conditional knockout lines reported here will be useful tools for further functional analyses of Kiaa0319.Electronic supplementary materialThe online version of this article (doi:10.1007/s00429-016-1282-1) contains supplementary material, which is available to authorized users.

The dyslexia susceptibility KIAA0319 gene shows a highly specific expression pattern during zebrafish development supporting a role beyond neuronal migration

“…Both KIAA0319 and KIAA0319L have been implicated in neuronal migration following knockdown experiments that specifically targeted neurons at the early stages of brain development using in utero shRNA in rats (11,(26)(27)(28)(29). However, knockout (KO) mouse models do not display any cortical abnormalities that could be explained by defective neuronal migration (30,31). Instead, the KO mice presented auditory system defects (31) in line with observations reported in adult rats that underwent KIAA0319 knock-down in utero (27,32,33).…”

The neuronal migration hypothesis of dyslexia: A critical evaluation 30 years on

“…However, examination of the brains of each of these KO mice revealed no abnormalities in the organisation of neurons in the neocortex. Kiaa0319 (Figure a; Martinez‐Garay et al., ), Dcdc2 (Wang et al., ), Dyx1c1 (Rendall, Tarkar, Contreras‐Mora, LoTurco, & Fitch, ) and Kiaa0319L (Guidi et al., ) displayed the normal layered structuring in the neocortex and no evidence of layer I ectopias, PVNH or other migration problems, contrary to what would be expected from the shRNA knockdown experiments conducted in rats. These studies are shown in Table .…”

“…Doublecortin family members are known to have partially overlapping functions (Deuel et al., ; Koizumi, Tanaka, & Gleeson, ) and it is possible that the absence of migration defects in Dcdc2 KOs may be due to compensation by the Dcx gene. This could also explain the lack of defects observed at least in Kiaa0319 or Kiaa0319L KOs (Guidi et al., ; Martinez‐Garay et al., ). But this possibility was ruled out by examining double Kiaa0319; Kiaa0319L KO mice (Guidi et al., ), where both proteins are fully absent.…”

“…Experiments have been conducted with this method to interrogate the function of Dcdc2 , Kiaa0319 and the joint effect of Kiaa0319 and Kiaa0319L : the acute disruption did not lead to observable problems in migration in any of the three cases (Figure b; Guidi et al., ; Martinez‐Garay et al., ; Wang et al., ). These results are in stark contrast to the findings obtained with shRNA for each of these genes (Meng et al., ; Paracchini et al., ; Platt et al., ).…”

The dyslexia susceptibility KIAA0319 gene shows a specific expression pattern during zebrafish development supporting a role beyond neuronal migration

“…Both KIAA0319 and KIAA0319L have been implicated in neuronal migration following knockdown experiments that specifically targeted neurons at the early stages of brain development using in utero shRNA in rats (Adler et al, ; Paracchini et al, ; Peschansky et al, ; Platt et al, ; Szalkowski et al, ). However, knockout (KO) mouse models do not display any cortical abnormalities that could be explained by defective neuronal migration (Guidi et al, ; Martinez‐Garay et al, ). Instead, the KO mice presented auditory system defects (Guidi et al, ) in line with observations reported in adult rats that underwent KIAA0319 knock‐down in utero (Centanni et al, ; Centanni et al, ; Szalkowski et al, ).…”