Elsevier

Neuroscience

Volume 143, Issue 2, 1 December 2006, Pages 515-522
Neuroscience

Developmental neuroscience
DYX1C1 functions in neuronal migration in developing neocortex

https://doi.org/10.1016/j.neuroscience.2006.08.022Get rights and content

Abstract

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.

Section snippets

In utero electroporation

In utero transfection and RNAi methods were applied to embryonic rats as described previously (Bai et al., 2003). Briefly, pregnant Wistar rats (Charles River Laboratories, Wilmington, MA, USA), gestational day 14, were anesthetized with ketamine/xylazine (100/10 mixture, 0.1 mg/g, intraperitoneally). Microinjections of plasmid mixtures into the lateral cerebral ventricles of E14 embryos were made through the uterine wall via pulled glass capillary pipettes. One microliter to 1.5 μl of plasmid

RNAi of DYX1C1 in embryonic neocortex disrupts neuronal migration

In order to test whether DYX1C1 functions in neuronal migration, we produced shRNA vectors capable of decreasing heterologously expressed DYX1C1 protein by 30–70% in Cos7 cells as determined by Western blot analysis. The effect of these shRNAs on neuronal migration in vivo was assessed by the in utero electroporation and RNAi method (Bai et al., 2003). With this approach, cells are initially transfected and labeled at the VZ surface and then over the course of several days transfected cells

Discussion

The results from this study indicate that DYX1C1 plays a role in the migration of neocortical neurons and more specifically is required for the transition out of the multipolar stage of migration. Other proteins have been recently shown to be important for transition out of the multipolar stage of migration. For example, Dcx, Lis1, and FlnA function in transition out of the multipolar stage (Bai et al 2003, Nagano et al 2004, Tsai et al 2005), and this has led to the hypothesis that transition

Acknowledgments

All work was supported by grants from the NIH, MH056524, and HD20806. J.K. was supported by Academy of Finland, Sigrid Juselius Foundation, Sohlberg Foundation and Swedish Research Council. We thank Ami Okada and Sue McConnell for the pCA-eGFPgapm4 plasmid and David Turned for the pU6-BT4HP1 shRNA plasmid.

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      Citation Excerpt :

      It is the a 78-kb gene located in chromosome 15 region and is first implicated dyslexia candidate following study of a Finnish family transmitting a chromosomal translocation at 15q21 (Bates et al., 2010). The main role of this gene has been implicated in the neuronal migration during the development of neocortex (Wang et al., 2006). A study in India looked at four SNPs corresponding to DYX1C1 candidate gene in 52 dyslexic children and 51 control children of 8–14 years of age using DNA sequencing and found no association of four studied SNPs (Saviour et al., 2008).

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    These authors contributed equally to the work.

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