Developmental Cell
Volume 42, Issue 5, 11 September 2017, Pages 445-461.e5
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Article
Cerebral Vein Malformations Result from Loss of Twist1 Expression and BMP Signaling from Skull Progenitor Cells and Dura

https://doi.org/10.1016/j.devcel.2017.07.027Get rights and content
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Highlights

  • Humans with TWIST1 mutations and craniosynostosis have dural cerebral vein defects

  • Twist1 loss in osteoprogenitor cells and dura causes skull and vascular defects

  • Twist1 mouse mutants show loss of Bmp2/4 expression in osteogenic mesoderm and dura

  • Bmp2/4 loss from mesoderm-derived preosteoblasts/dura causes skull and vein defects

Summary

Dural cerebral veins (CV) are required for cerebrospinal fluid reabsorption and brain homeostasis, but mechanisms that regulate their growth and remodeling are unknown. We report molecular and cellular processes that regulate dural CV development in mammals and describe venous malformations in humans with craniosynostosis and TWIST1 mutations that are recapitulated in mouse models. Surprisingly, Twist1 is dispensable in endothelial cells but required for specification of osteoprogenitor cells that differentiate into preosteoblasts that produce bone morphogenetic proteins (BMPs). Inactivation of Bmp2 and Bmp4 in preosteoblasts and periosteal dura causes skull and CV malformations, similar to humans harboring TWIST1 mutations. Notably, arterial development appears normal, suggesting that morphogens from the skull and dura establish optimal venous networks independent from arterial influences. Collectively, our work establishes a paradigm whereby CV malformations result from primary or secondary loss of paracrine BMP signaling from preosteoblasts and dura, highlighting unique cellular interactions that influence tissue-specific angiogenesis in mammals.

Keywords

Twist1
BMP4
BMP2
craniosynostosis
venous angiogenesis
cerebral veins
coronal suture
ICP
osteoblast
skull

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