Tischfield Max A, 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
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.
Department of Radiology, Boston Children's Hospital, Boston, MA 02115, USA; Department of Radiology, Harvard Medical School, Boston, MA 02115, USA.
Dev Cell. 2017 Sep 11;42(5):445-461.e5. doi: 10.1016/j.devcel.2017.07.027. Epub 2017 Aug 30.
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.
硬脑膜脑静脉（CV）对于脑脊液重吸收和脑内环境稳定是必需的，但调节其生长和重塑的机制尚不清楚。我们报告了调节哺乳动物硬脑膜CV发育的分子和细胞过程，并描述了患有颅缝早闭和TWIST1突变的人类静脉畸形，这些在小鼠模型中得到了重现。令人惊讶的是，Twist1在内皮细胞中是可有可无的，但对于分化为产生骨形态发生蛋白（BMP）的前成骨细胞的骨祖细胞的特化是必需的。前成骨细胞和骨膜硬脑膜中Bmp2和Bmp4的失活会导致颅骨和CV畸形，类似于携带TWIST1突变的人类。值得注意的是，动脉发育似乎正常，这表明来自颅骨和硬脑膜的形态发生素建立了独立于动脉影响的最佳静脉网络。总的来说，我们的工作建立了一个范例，即CV畸形是由前成骨细胞和硬脑膜旁分泌BMP信号的原发性或继发性丧失导致的，突出了影响哺乳动物组织特异性血管生成的独特细胞相互作用。
