29959
Autism-Associated CHD8 Deficiency Impairs Axon Development and Migration of Cortical Neurons
Objectives: To reveal the expression pattern and important roles of Chd8 in mouse developing brain.
Methods: We examined the expression of CHD8 in human and mouse brains using both immunohistochemistry and RNA in situ hybridization. We performed in utero electroporation, neuronal culture, and biochemical analysis using RNAi to examine the functional consequences of CHD8 deficiency.
Results: We discovered that CHD8 is expressed highly in neurons and at low levels in glia cells in both humans and mice. Specifically, CHD8 is localized predominately in the nucleus of both MAP2 and parvalbumin positive neurons. In the developing mouse brain, expression of Chd8 peaks from E16 to E18 and then decreases significantly at P14 to adulthood. Knockdown of Chd8 results in the reduction of axon and dendritic growth, disruption of axon projections to the contralateral cortex, and delayed neuronal migration at E18.5 which is recovered by P3 and P7.
Conclusions: Our findings indicate an important role for CHD8 in dendritic and axon development and neuronal migration, and thus offer novel insights to further dissect the underlying molecular and circuit mechanisms of ASD caused by CHD8 deficiency.