DYX1C1 functions in neuronal migration in developing cortex

Department of Physiology and Neurobiology, University of Connecticut, Storrs, CT 06268, USA.
Neuroscience (Impact Factor: 3.36). 01/2007; 143(2):515-22. DOI: 10.1016/j.neuroscience.2006.08.022
Source: PubMed


Rodent homologues of two candidate dyslexia susceptibility genes, Kiaa0319 and Dcdc2, have been shown to play roles in neuronal migration in developing cerebral neocortex. This functional role is consistent with the hypothesis that dyslexia susceptibility is increased by interference with normal neural development. In this study we report that in utero RNA interference against the rat homolog of another candidate dyslexia susceptibility gene, DYX1C1, disrupts neuronal migration in developing neocortex. The disruption of migration can be rescued by concurrent overexpression of DYX1C1, indicating that the impairment is not due to off-target effects. Transfection of C- and N-terminal truncations of DYX1C1 shows that the C-terminal TPR domains determine DYX1C1 intracellular localization to cytoplasm and nucleus. RNAi rescue experiments using truncated versions of DYX1C1 further indicate that the C-terminus of DYX1C1 is necessary and sufficient to DYX1C1's function in migration. In conclusion, DYX1C1, similar to two other candidate dyslexia susceptibility genes, functions in neuronal migration in rat neocortex.

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    • "This processing pattern already in the newborns at risk for dyslexia suggests that there could be an early biological factor, likely genetic in nature, that would contribute to the development of the later language skills. The supposed genetic basis of dyslexia (for a review, see Wood & Grigorenko, 2001) has recently been documented to the single gene level via identification of candidate genes such as DYX1C1 (Taipale et al., 2003; Wang et al., 2006), DCDC2 (Meng et al., 2005), KIAA0319 (Cope et al., 2005; Paracchini et al., 2006), and ROBO1 (Andrews et al., 2006). As stated, for example, by Pennington (1991), genetic factors can conceivably alter brain development through a large number of different pathways, and the parameters of brain structure affected could be, for example, neuronal number, neuronal migration, and axonal connectivity, all of which are determined with few exceptions before birth. "

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    • "Furthermore, suppression of genes related to dyslexia (e.g., DCDC2, KIAA0319), autism spectrum disorder (ASD) (e.g., Auts2, CNTNAP2) and schizophrenia (e.g., SDCCAG8) disturbs neuronal migration, although it is unclear whether the neuronal migration defect is the main cause of the pathogenesis of these neurological and psychiatric disorders (Hannula-Jouppi et al., 2005; Kamiya et al., 2005; Meng et al., 2005; Paracchini et al., 2006; Wang et al., 2006; Kähler et al., 2008; Peñagarikano et al., 2011; O'roak et al., 2012; Zhang et al., 2013a; Hori et al., 2014; Insolera et al., 2014; La Fata et al., 2014) (Figure 1B). "
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    • "In particular, variations in DCDC2 were found to associate with wide-spread gray matter changes and reading-related brain activation (Cope et al., 2012; Meda et al., 2008). Moreover, variations in DCDC2, DYX1C1, and KIAA0319 were shown to affect temporo-parietal white matter (Darki, Peyrard-Janvid, Matsson, Kere, & Klingberg, 2012; Marino et al., 2014), even though these structural features may be only indirectly affected by genetically determined alterations in neuronal migration (Meng et al., 2005; Paracchini et al., 2006; Wang et al., 2006). "
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