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

Friday, May 12, 2017: 5:00 PM-6:30 PM
Golden Gate Ballroom (Marriott Marquis Hotel)
M. Goto1, M. Mizuno2, A. Matsumoto1, Z. Yang1, E. F. Jimbo1, H. Tabata2, K. I. Nagata2 and T. Yamagata1, (1)Jichi Medical University, Shimotsuke, Japan, (2)Developmental Research, Aichi Human Service Center, Kasugai, Japan
Background: Autism spectrum disorder (ASD) is frequently accompanied by comorbid conditions, and associated with problems in the early developmental period including hyperactivity, panic, self-injury and sleep disturbance. Among them, sleep disruption such as insomnia or a short sleep cycle is one of the most common and distressed problems. In our previous study (Yang et al. 2015), we screened 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 (Nuclear receptor subfamily 1 group D member 1). Thus, circadian-relevant genes likely represent impaired molecular clock mechanisms that potentially contribute to the etiology of ASD. Meanwhile, NR1D1 is located on 17q11.2, which was shown to be a region susceptible to ASD. As for the neuronal function, while synaptic activity induced the distribution of Nr1d1 to the spine and dendrite in wild-type mice, Nr1d1-knockout mice displayed abnormal behaviors such as marked hyperactivity, impaired response habituation in novel environments, deficient contextual memories and impairment in nest-building ability. The above observations raise the possibility that NR1D1 is crucial for synaptic functions and is a causal gene candidate for ASD and other neurodevelopmental disorders.

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.