Reading disability (RD) or dyslexia is the most common learning disorder in children. While 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 three years four candidate dyslexia susceptibility genes have been proposed (DYX1C1, KIAA0319, DCDC2 and ROBO1), and all four play roles in neuronal development. Rodent homologs of three of these, Dyx1c1, Kiaa0319 and Dcdc2 have been shown to play a role in neuronal migration in developing neocortex, and Robo1 was previously shown to be important for axon growth and guidance. The first three aims of the project will further define the cellular and developmental roles of Kiaa0319 and Dcdc2, the two genes currently with strongest genetic support as dyslexia susceptibility genes. These three aims are to determine the components of neuronal migration regulated by dcdc2 and kiaa0319, to determine functional links between kiaa0319 and dcdc2 in neuronal migration, and to determine the functionally necessary protein domains of dcdc2 and kiaa0319.
The aims will be carried out by a combination of in utero RNAi, imaging, and cell culture approaches. Novel combinatorial methods of RNAi and electroporation are proposed to investigate interaction between Kiaa0319 and Dcdc2. Finally, in collaboration with groups currently working on identifying additional dyslexia susceptibility genes in human populations, we propose to test the developmental roles of new candidate dyslexia susceptibility genes in neuronal migration and development. Together, results form these experiments will reveal the cellular functions of candidate dyslexia susceptibility genes in neuronal development, and this should contribute to an eventual understanding of the underlying causes of this learning disorder. Project Narrative: Reading disability (RD) or dyslexia is the most common learning disorder in children. While 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. Results form these proposed experiments will reveal the cellular functions of candidate dyslexia susceptibility genes in neuronal development, and this should contribute to an eventual understanding of the underlying causes of this learning disorder.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD055655-03
Application #
7764652
Study Section
Special Emphasis Panel (ZRG1-BDCN-N (02))
Program Officer
Miller, Brett
Project Start
2008-03-01
Project End
2013-01-31
Budget Start
2010-02-01
Budget End
2011-01-31
Support Year
3
Fiscal Year
2010
Total Cost
$321,874
Indirect Cost
Name
University of Connecticut
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
614209054
City
Storrs-Mansfield
State
CT
Country
United States
Zip Code
06269
Che, Alicia; Truong, Dongnhu T; Fitch, R Holly et al. (2016) Mutation of the Dyslexia-Associated Gene Dcdc2 Enhances Glutamatergic Synaptic Transmission Between Layer 4 Neurons in Mouse Neocortex. Cereb Cortex 26:3705-3718
Chen, Fuyi; Becker, Albert; LoTurco, Joseph (2016) Overview of Transgenic Glioblastoma and Oligoastrocytoma CNS Models and Their Utility in Drug Discovery. Curr Protoc Pharmacol 72:14.37.1-12
Chen, Fuyi; Rosiene, Joel; Che, Alicia et al. (2015) Tracking and transforming neocortical progenitors by CRISPR/Cas9 gene targeting and piggyBac transposase lineage labeling. Development 142:3601-11
Fekete, Christopher D; Chiou, Tzu-Ting; Miralles, Celia P et al. (2015) In vivo clonal overexpression of neuroligin 3 and neuroligin 2 in neurons of the rat cerebral cortex: Differential effects on GABAergic synapses and neuronal migration. J Comp Neurol 523:1359-78
Che, Alicia; Girgenti, Matthew J; LoTurco, Joseph (2014) The dyslexia-associated gene DCDC2 is required for spike-timing precision in mouse neocortex. Biol Psychiatry 76:387-96
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
Glasgow, Stacey M; Zhu, Wenyi; Stolt, C Claus et al. (2014) Mutual antagonism between Sox10 and NFIA regulates diversification of glial lineages and glioma subtypes. Nat Neurosci 17:1322-9
Chen, Fuyi; Becker, Albert J; LoTurco, Joseph J (2014) Contribution of tumor heterogeneity in a new animal model of CNS tumors. Mol Cancer Res 12:742-53
Chen, Fuyi; Maher, Brady J; LoTurco, Joseph J (2014) piggyBac transposon-mediated cellular transgenesis in mammalian forebrain by in utero electroporation. Cold Spring Harb Protoc 2014:741-9
Centanni, Tracy M; Chen, Fuyi; Booker, Anne M et al. (2014) Speech sound processing deficits and training-induced neural plasticity in rats with dyslexia gene knockdown. PLoS One 9:e98439

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