Role of a Circadian-Relevant Gene, NR1D1, in the Brain Development: Possible Involvement in the Pathophysiology of Autism Spectrum Disorders

Background: In our previous study, we screened autism spectrum disorder (ASD) patients with and without sleep disorders for mutations in the coding regions of circadian-relevant genes, and detected mutations in several clock genes including NR1D1. Here, we further screened ASD patients for NR1D1 mutations and identified three novel mutations including a de novo heterozygous c.1499G>A (p.R500H).

Objectives: We analyzed the role of Nr1d1 in the development of mouse cerebral cortex.

Methods: We examined the pathophysiological significance of Nr1d1 by the acute knockdown or mutant expression in mouse brain with in utero electroporation.

Results: Acute knockdown of mouse Nr1d1 with 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 characteristic abnormal migration phenotypes of Nr1d1-deficient cortical neurons. When Nr1d1 was knocked down, axon extension and dendritic arbor formation of cortical neurons were also suppressed while proliferation of neuronal progenitors and stem cells at the ventricular zone was not affected. Taken together, Nr1d1 was found to play a pivotal role in corticogenesis via regulation of excitatory neuron migration and synaptic network formation.

Conclusions: The results suggest that functional defects in NR1D1 may relate to ASD etiology and pathophysiology.