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Twist1 Mutation And Environmental Factors Synergistically Exacerbate Craniosynostosis
Eloise Stanton, BA1,2, Mark Urata, MD, DDS2,3, Yang Chai, DDS, PhD4.
1Keck School of Medicine, Los Angeles, CA, USA, 2Children's Hospital Los Angeles, Los Angeles, CA, USA, 3Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA, 4Ostrow School of Dentistry of the University of Southern California, Los Angeles, CA, USA.

PURPOSE: Craniosynostosis, the premature closure of calvarial sutures, leads to debilitating neurologic dysfunction. TWIST1 gene mutation leads to Saethre-Chotzen syndrome, characterized by unilateral or bilateral coronal synostosis. Recently, studies have shown that in utero exposure to a serotonin selective reuptake inhibitor (SSRI), citalopram, increases the incidence of craniosynostosis in mice coupled with depletion of Gli1+ mesenchymal stem cells (MSCs), suggesting environmental risk factors may interplay with genetic mutations in craniosynostosis etiology. In this study, we sought to determine how Twist1 mutation interacts with maternal usage of citalopram to disrupt cranial suture MSCs, leading to craniosynostosis.
METHODS: Twist1+/- mutant mice with or without in utero citalopram exposure (20 mg/kg per day) were generated, including (1) wild type (WT) (n=14), (2) Twist1+/- (n=150), (3) WT + citalopram (n=, (44) Twist1+/- + citalopram (n=30). MicroCT analysis was performed at P14 to examine the extent of calvarial suture fusion since the coronal suture typically completes fusion at P9-13 in Twist1+/- mice. Histological analysis was completed to confirm suture fusion. RNAscope was also conducted to allow for quantitative molecular analysis.
RESULTS: In utero exposure to citalopram on the background of Twist1+/- led to increased aberrant suture fusion and skull deformation. WT mice had 0% cranial suture fusion. Twist1+/- mice without citalopram had between 70-80% suture fusion. WT mice with citalopram exposure had 36.4% suture fusion or skull dysmorphology. Importantly, Twist1+/- mice with in utero exposure to citalopram had the highest rate of suture fusion, 93.3%. Histological analysis of the craniosynostotic mice treated with citalopram also demonstrated lack of suture patency (Figure 1). In addition, RNAscope gene expression analyses demonstrated that Gli1+ cells were diminished in mice exposed to citalopram in utero.
CONCLUSION: Exposure to citalopram in utero leads to an increased frequency of craniosynostosis both in WT and Twist1+/- mice. Our preliminary data suggests that there is a combinatorial effect of genetic mutations and environmental factor in the development of craniosynostosis. Developing a fuller understanding of the signaling mechanisms that mediate suture morphogenesis and underlie the gene-environment interactions will provide crucial insight into the pathophysiology of this devastating disease.
This study was supported by grants from the National Institute of Dental and Craniofacial Research, NIH (R01 DE026339, R01 DE012711, R01 DE022503, and U24 026914 to Y.C.).


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