The specific causes of dyslexia are not yet known. Recent genetic and neurobiological studies strengthen a working hypothesis that dyslexia is caused by early developmental disruptions that subsequently cause functional impairments in neocortical circuits. Within the past four years, 4 candidate dyslexia susceptibility genes with roles in neuronal development have been proposed (DYX1C1, KIAA0319, DCDC2 and ROBO1). Rodent homologs of three of these, Dyxld, Kiaa0319 and Dcdc2 have been shown by our group to play a role in neuronal migration in'developing neocortex, and Robol was previously shown to be important for axon growth and guidance. The three aims of this project will further define the cellular and developmental roles of Dyxld. The proposed experiments will define the components of neuronal migration and differentiation regulated by Dyxld, and identify functional links between Dyxld and other proteins essential to migration.
The aims will be executed by a combination of in utero RNAi, imaging, protein-protein interaction assays, and cell culture approaches. Novel in vivo conditional RNAi and overexpression methods will be used to explore the temporal dependence of Dyxld function, and potential developmental reversibility of Dyx1c1 dysfunction. Together, these experiments will lead to a comprehensive molecular and cellular understanding of the function of a gene linked to reading and learning disability.
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|Siddiqi, Faez; Chen, Fuyi; Aron, Abraham W et al. (2014) Fate mapping by piggyBac transposase reveals that neocortical GLAST+ progenitors generate more astrocytes than Nestin+ progenitors in rat neocortex. Cereb Cortex 24:508-20|
|Centanni, T M; Booker, A B; Sloan, A M et al. (2014) Knockdown of the dyslexia-associated gene Kiaa0319 impairs temporal responses to speech stimuli in rat primary auditory cortex. Cereb Cortex 24:1753-66|
|Truong, Dongnhu T; Bonet, Ashley; Rendall, Amanda R et al. (2013) A behavioral evaluation of sex differences in a mouse model of severe neuronal migration disorder. PLoS One 8:e73144|
|Platt, M P; Adler, W T; Mehlhorn, A J et al. (2013) Embryonic disruption of the candidate dyslexia susceptibility gene homolog Kiaa0319-like results in neuronal migration disorders. Neuroscience 248C:585-593|
|Szalkowski, Caitlin E; Fiondella, Christopher F; Truong, Dongnhu T et al. (2013) The effects of Kiaa0319 knockdown on cortical and subcortical anatomy in male rats. Int J Dev Neurosci 31:116-22|
|Szalkowski, Caitlin E; Booker, Anne B; Truong, Dongnhu T et al. (2013) Knockdown of the candidate dyslexia susceptibility gene homolog dyx1c1 in rodents: effects on auditory processing, visual attention, and cortical and thalamic anatomy. Dev Neurosci 35:50-68|
|Tarkar, Aarti; Loges, Niki T; Slagle, Christopher E et al. (2013) DYX1C1 is required for axonemal dynein assembly and ciliary motility. Nat Genet 45:995-1003|
|LoTurco, Joseph J; Tarkar, Aarti (2013) DYX1C1 placed in a molecular context. Biol Psychiatry 73:497-8|
|Adler, William T; Platt, Maryann P; Mehlhorn, Alison J et al. (2013) Position of neocortical neurons transfected at different gestational ages with shRNA targeted against candidate dyslexia susceptibility genes. PLoS One 8:e65179|
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