Cerebral Vein Malformations Result from Loss of Twist1 Expression and BMP Signaling from Skull Progenitor Cells and Dura

Max A. Tischfield, Caroline D. Robson, Nicole M. Gilette, Shek Man Chim, Folasade A. Sofela, Michelle M. DeLisle, Alon Gelber, Brenda J. Barry, Sarah MacKinnon, Linda R. Dagi, Jeremy Nathans, Elizabeth C. Engle

Research output: Contribution to journalArticlepeer-review

17 Scopus citations


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. By characterizing dural cerebral vein malformations in TWIST1 mutation-positive humans and mouse models with craniosynostosis, Tischfield et al. report that cerebral vein angiogenesis requires paracrine BMP signaling from skull preosteoblasts and periosteal dura. The effects are independent from arterial influences and highlight unique cellular interactions that pattern tissue-specific vascular networks.

Original languageEnglish (US)
Pages (from-to)445-461.e5
JournalDevelopmental Cell
Issue number5
StatePublished - Sep 11 2017


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

ASJC Scopus subject areas

  • Molecular Biology
  • General Biochemistry, Genetics and Molecular Biology
  • Developmental Biology
  • Cell Biology


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