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Dev Cell. 2017 Sep 11;42(5):445-461.e5. doi: 10.1016/j.devcel.2017.07.027. Epub 2017 Aug 30.

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

Author information

1
Department of Neurology, Boston Children's Hospital, Boston, MA 02115, USA; FM Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA 02115, USA; Department of Neurology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: max.tischfield@gmail.com.
2
Department of Radiology, Boston Children's Hospital, Boston, MA 02115, USA; Department of Radiology, Harvard Medical School, Boston, MA 02115, USA.
3
Department of Neurology, Boston Children's Hospital, Boston, MA 02115, USA.
4
Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA 02115, USA.
5
Department of Neurology, Boston Children's Hospital, Boston, MA 02115, USA; FM Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA 02115, USA.
6
Department of Neurology, Boston Children's Hospital, Boston, MA 02115, USA; FM Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA 02115, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
7
Department of Ophthalmology, Boston Children's Hospital, Boston, MA 02115, USA.
8
Department of Ophthalmology, Boston Children's Hospital, Boston, MA 02115, USA; Department of Ophthalmology, Harvard Medical School, Boston, MA 02115, USA.
9
Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA; Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
10
Department of Neurology, Boston Children's Hospital, Boston, MA 02115, USA; Department of Ophthalmology, Boston Children's Hospital, Boston, MA 02115, USA; FM Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA 02115, USA; Department of Neurology, Harvard Medical School, Boston, MA 02115, USA; Department of Ophthalmology, Harvard Medical School, Boston, MA 02115, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA. Electronic address: elizabeth.engle@childrens.harvard.edu.

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.

KEYWORDS:

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

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PMID:
28844842
PMCID:
PMC5595652
DOI:
10.1016/j.devcel.2017.07.027
[Indexed for MEDLINE]
Free PMC Article

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