Background: Clinical genome-wide analysis identified NOMO1 in human chromosome 16p13.11 as a candidate gene associated with neuropsychiatric disorders such as autism, schizophrenia and epilepsy. However, the important contributions underlying NOMO1 deficiency resulting in neuropsychiatric disorders is not understand, and the molecular and pathogenesis mechanisms of nomo1 gene are unclear. Therefore, it is necessary to construct animal models to systematically study the effects of nomo1 deficiency on neuropsychiatric system and explore pathogenic molecular mechanism of diseases.
Methods: We developed a viable vertebrate model of loss-of-function of nomo1 using CRISPR/Cas9 and studied the characterization of nomo1 mutant zebrafish. Phenotypic research was performed in developing nomo1 mutant zebrafish, including morphological measurements, behavioral tests, and functional mechanism analyses.
Results: The nomo1 loss-of-function zebrafish model accurately recapitulated key neuropsychiatric disorders traits. The mutant zebrafish showed decreased locomotion in the larval stage (7 dpf), increased spontaneous movement in infancy (15 dpf and 30 dpf), and social defects and repetitive behaviors in adolescence (2 mpf). More importantly, we demonstrated that these behavioral phenotypes stem from abnormal brain structure and neurotransmitter metabolism. Transcriptome analysis provided insights for studying the functional mechanism of nomo1 pathogenesis. Further results revealed that the neuroactive drug PTZ recovered the decreased locomotion phenotype in larval zebrafish, which provides functional basis for the exploration of drug sensitivity and intervention in behavioral phenotypes of nomo1 mutant zebrafish.
Conclusion: This study firstly reveal the functional evidence that loss-of-function of nomo1 elicits neuropsychiatric disorders, and emphasize the relationship between nomo1 deficiency and neuropsychiatric disorders from the perspectives of behavioral phenotypes, brain development, and neurotransmitter metabolism.
Limitation: The behavioral phenotype intervention of neuroactive drug in nomo1-/-zebrafish can be directly translated to the behavior of human associated diseases need further study.