Krüppel-like factor 7 deficiency causes autistic-like behavior in mice via regulating Clock gene

BACKGROUND: Krüppel-like factor 7 (klf7), a transcription factor in the nervous system to regulate cell proliferation and differentiation, has been recently identified as a causal gene for autism spectrum disorder (ASD), but the mechanism behind remains unknown. RESULT: To uncover this mechanism, in this study we characterized the involvement of klf7 in circadian rhythm by knocking down klf7 in N2A cells and examining the rhythmic expression of circadian genes, especially Clock gene. We constructed klf7(−/−) mice and then investigated into klf7 regulation on the expression of rhythm genes in vivo as well as the use of melatonin to rescue the autism behavior. Our results illustrated that circadian rhythm was disrupted in klf7 knockdown cells and that klf7(−/−) mice showed autism-like behavior. Also, we found that Clock gene was downregulated in the brain of these klf7(−/−) mice and that the downstream rhythm genes of Clock were disturbed. Melatonin, as a circadian regulation drug, could regulate the expression level and amplitude of rhythm genes in klf7 knockout cells and further rescue the autistic behavior of klf7(−/−) mice. CONCLUSION: Klf7 deficiency causes ASD by disrupting circadian rhythm related genes to trigger rhythm oscillations. To treat ASD, maintaining circadian homeostasis is promising with the use of melatonin.