Journal
MOLECULAR NEUROBIOLOGY
Volume 56, Issue 5, Pages 3780-3795Publisher
SPRINGER
DOI: 10.1007/s12035-018-1297-0
Keywords
Cognitive function; Cortical neurogenesis; Lin28; Neurite outgrowth; Neurodevelopmental disorders
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Funding
- National Research Foundation of Korea (NRF) - Korean government [NRF-2017R1D1A1B03029812]
- Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI) - Ministry of Health Welfare [HI15C2854]
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Many neurodevelopmental disorders feature learning and memory difficulties. Regulation of neurite outgrowth during development is critical for neural plasticity and memory function. Here, we show a novel regulator of neurite outgrowth during cortical neurogenesis, Lin28, which is an RNA-binding protein. Persistent Lin28 upregulation by in utero electroporation at E14.5 resulted in neurite underdevelopment during cortical neurogenesis. We also showed that Lin28-overexpressing cells had an attenuated response to excitatory inputs and altered membrane properties including higher input resistance, slower action potential repolarization, and smaller hyperpolarization-activated cation currents, supporting impaired neuronal functionality in Lin28-electroporated mice. When we ameliorated perturbed Lin28 expression by siRNA, Lin28-induced neurite underdevelopment was rescued with reduction of Lin28-downstream molecules, high mobility group AT-Hook 2, and insulin-like growth factor 1 receptor. Finally, Lin28-electroporated mice showed significant memory deficits as assessed by the Morris water maze test. Taken together, these findings demonstrate a new role and the essential requirement of Lin28 in developmental control of neurite outgrowth, which has an impact on synaptic plasticity and spatial memory. These findings suggest that targeting Lin28 may attenuate intellectual disabilities by correction of impaired dendritic complexity, providing a novel therapeutic candidate for treating neurodevelopmental disorders.
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