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Role of a Circadian-Relevant Gene, NR1D1, in Brain Development: Possible Involvement in the Pathophysiology of Autism Spectrum Disorder
Objectives: We elucidated the role of Nr1d1 in the corticogenesis and contribution to ASD.
Methods: Sequence analyses of NR1D1 was done in ASD patients to detect mutation. And also, we performed in vivo analyses; in situ hybridization of Nr1d1 in developing mouse brain, and time-lapse imaging of migration of Nr1d1-deficient neurons.
Results: We identified three new substitutions, including a de novo heterozygous mutation, c.1499G>A (p.R500H) in ASD patients that was not detected in control individuals. We then examined the role of NR1D1 in the development of the mouse cerebral cortex. Acute knockdown of mouse NR1D1 by in utero electroporation caused abnormal positioning of cortical neurons during corticogenesis. This aberrant phenotype was rescued by wild type NR1D1, but not by the c.1499G>A mutant. Time-lapse imaging revealed that the abnormal positioning was due to impaired migration. Moreover, knockdown of NR1D1 also suppressed axon extension and dendritic arbor formation of cortical neurons, while the proliferation of neuronal progenitors and stem cells at the ventricular zone was not affected.
Conclusions: NR1D1 plays a pivotal role in corticogenesis via regulation of excitatory neuron migration and synaptic network formation, besides the role in circadian rhythm formation. Addition to the detection of de novo mutation in ASD patient, functional defects in NR1D1 suggested to relate to ASD pathophysiology.