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The corpus callosum connects the left and right hemispheres and functions in integration, transfer and processing of the sensory, motor and cognitive information from both
hemispheres. Defects in the corpus callosum is the most common pathological feature among neurological diseases including neurodegenerative, neurodevelopmental and neuropsychiatric diseases. Corpus callosum atrophy is strongly associated with cognitive decline in neurodegenerative diseases, whereas partial agenesis of the corpus callosum is commonly seen in neurodevelopmental and psychiatric disorders, suggesting a possibility for the callosal projection neuron with an intrinsic vulnerable characteristic. However, the cause of predisposition to malformation or breakdown of the corpus callosum in neurological diseases remains undetermined. The cognitive impairments of myotonic dystrophy type 1 (DM1) include mental retardation, autism spectrum disorder (ASD), depression, attention deficit hyperactivity disorders (ADHD), and neurodegeneration. Hypoplasia and atrophy of the corpus callosum are the major feature of DM1 brain. The genetic basis of DM1 is caused by an expansion of CTG repeats in the 3’ untranslated region (UTR) of the Dystrophia
Myotonica Protein Kinase (DMPK) gene. DMPK mRNA containing expanded CUG repeats accumulates in nuclear foci and disrupts functions of at least two families of RNA binding proteins: muscleblind like (MBNL) and CUGBP Elav-like family member (CELF) proteins. To understand the impact of expanded CUG (CUGexp) RNA on the cortical development, we established a mouse model, EpA960/Emx1IREScre, for expression of CUGexp RNA in neural progenitors of the dorsal telencephalon during neurogenesis. EpA960/Emx1IREScre animals exhibited features of congenital DM1, including reduced brain size, corpus callosum hypoplasia, anxiety-like behavior, and impairments in social interaction, learning and memory. Expression of CUGexp RNA impaired the proliferation of neural progenitors and induced their cell death, resulting in reduced generation of callosal projection neurons
(CPNs). To elucidate the mechanism underlying CUGexp RNA–induced cell death, we identified an association with CUGexp RNA–induced metabolic dysregulation. Detailed
characterization of this metabolic dysregulation is currently in progress.