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

Max 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 journalArticle

5 Citations (Scopus)

Abstract

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
Volume42
Issue number5
DOIs
StatePublished - Sep 11 2017

Fingerprint

Cerebral Veins
Bone Morphogenetic Proteins
Skull
Mammals
Stem Cells
Tissue
Cerebrospinal fluid
Craniosynostoses
Endothelial cells
Mutation
Brain
Specifications
Blood Vessels
Cerebrospinal Fluid
Homeostasis
Endothelial Cells
Growth

All Science Journal Classification (ASJC) codes

  • Developmental Biology

Keywords

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

Cite this

Tischfield, Max ; Robson, Caroline D. ; Gilette, Nicole M. ; Chim, Shek Man ; Sofela, Folasade A. ; DeLisle, Michelle M. ; Gelber, Alon ; Barry, Brenda J. ; MacKinnon, Sarah ; Dagi, Linda R. ; Nathans, Jeremy ; Engle, Elizabeth C. / Cerebral Vein Malformations Result from Loss of Twist1 Expression and BMP Signaling from Skull Progenitor Cells and Dura. In: Developmental Cell. 2017 ; Vol. 42, No. 5. pp. 445-461.e5.
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abstract = "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.",
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Tischfield, M, Robson, CD, Gilette, NM, Chim, SM, Sofela, FA, DeLisle, MM, Gelber, A, Barry, BJ, MacKinnon, S, Dagi, LR, Nathans, J & Engle, EC 2017, 'Cerebral Vein Malformations Result from Loss of Twist1 Expression and BMP Signaling from Skull Progenitor Cells and Dura', Developmental Cell, vol. 42, no. 5, pp. 445-461.e5. https://doi.org/10.1016/j.devcel.2017.07.027

Cerebral Vein Malformations Result from Loss of Twist1 Expression and BMP Signaling from Skull Progenitor Cells and Dura. / Tischfield, Max; Robson, Caroline D.; Gilette, Nicole M.; Chim, Shek Man; Sofela, Folasade A.; DeLisle, Michelle M.; Gelber, Alon; Barry, Brenda J.; MacKinnon, Sarah; Dagi, Linda R.; Nathans, Jeremy; Engle, Elizabeth C.

In: Developmental Cell, Vol. 42, No. 5, 11.09.2017, p. 445-461.e5.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Cerebral Vein Malformations Result from Loss of Twist1 Expression and BMP Signaling from Skull Progenitor Cells and Dura

AU - Tischfield, Max

AU - Robson, Caroline D.

AU - Gilette, Nicole M.

AU - Chim, Shek Man

AU - Sofela, Folasade A.

AU - DeLisle, Michelle M.

AU - Gelber, Alon

AU - Barry, Brenda J.

AU - MacKinnon, Sarah

AU - Dagi, Linda R.

AU - Nathans, Jeremy

AU - Engle, Elizabeth C.

PY - 2017/9/11

Y1 - 2017/9/11

N2 - 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.

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KW - BMP2

KW - BMP4

KW - ICP

KW - Twist1

KW - cerebral veins

KW - coronal suture

KW - craniosynostosis

KW - osteoblast

KW - skull

KW - venous angiogenesis

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