Mechanisms and rescue of craniosynostosis associated with gene-environment interaction

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PROJECT SUMMARY / ABSTRACT Craniosynostosis is a craniofacial disorder characterized by the premature fusion of cranial sutures with defective mesenchymal stem cells (MSCs). Patients with severe craniosynostosis often have intellectual disabilities (IDs). Both genetic mutations and environmental factors have been linked to craniosynostosis coupled with MSC depletion. We propose to determine gene-environment interaction mechanisms in craniosynostosis by addressing how craniosynostosis disease genes Twist1 and Tcf12 interplay with an environmental risk factor, namely maternal usage of the antidepressant citalopram. Importantly, we aim to establish a MSC-based therapeutic strategy to mitigate both skull dysmorphology and neurocognitive dysfunctions in craniosynostosis. This is innovative and significant because we have little understanding of environmental factors and gene-environment interactions in craniosynostosis, and new treatments for this devastating disorder are urgently needed. Neurocognitive functions have been largely neglected in studies of animal models of craniosynostosis, although cognitive abnormalities such as IDs have been frequently observed in craniosynostosis patients. The only current treatment option for craniosynostosis is complex surgery, which is invasive and often requires re-operation due to the calvarial bones fusing again. Our MSC- based cranial suture regeneration approach is less invasive, avoids re-fusion, corrects skull dysmorphology, restores elevated intracranial pressure, and reduces neurocognitive dysfunctions later in life in a clinically relevant Twist1+/- mouse model of craniosynostosis. Gli1+ MSC depletion is observed both in Twist1+/- mice and in those with maternal exposure to citalopram. Citalopram is a selective serotonin reuptake inhibitor (SSRI), which is the most commonly prescribed class of antidepressant drugs. Maternal SSRI usage is also known as an environmental risk factor for craniosynostosis in humans. These results lead to the hypothesis that Twist1 and Tcf12 mutations may interplay with citalopram in exacerbating skull and neurocognitive defects in craniosynostosis, which will be tested in Aim 1. Aim 2 will determine cellular and molecular mechanisms by which gene mutations and maternal citalopram exposure act together to cause craniosynostosis. Aim 3 will use our newly developed MSC-based suture regeneration approach to determine whether and how MSC implantation mitigates skull and neurocognitive dysfunctions in craniosynostosis caused by gene mutations, citalopram, and their interactions. Collectively, our proposed studies build upon our previous discoveries, and our findings will be highly significant for improving the understanding of mechanisms underlying gene- environment interplay in craniosynostosis; it offers a unique opportunity for improving treatment of infants with craniosynostosis.