Mechanisms and rescue of craniosynostosis associated with gene-environment interaction

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.

Grant Number: 5R01DE030901-05
NIH Institute/Center: NIH
Principal Investigator: Jianfu Chen