Developmental Cell
Volume 18, Issue 1, 19 January 2010, Pages 25-38
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Article
Local Protease Signaling Contributes to Neural Tube Closure in the Mouse Embryo

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Summary

We report an unexpected role for protease signaling in neural tube closure and the formation of the central nervous system. Mouse embryos lacking protease-activated receptors 1 and 2 showed defective hindbrain and posterior neuropore closure and developed exencephaly and spina bifida, important human congenital anomalies. Par1 and Par2 were expressed in surface ectoderm, and Par2 was expressed selectively along the line of closure. Ablation of Gi/z and Rac1 function in these Par2-expressing cells disrupted neural tube closure, further implicating G protein-coupled receptors and identifying a likely effector pathway. Cluster analysis of protease and Par2 expression patterns revealed a group of membrane-tethered proteases often coexpressed with Par2. Among these, matriptase activated Par2 with picomolar potency, and hepsin and prostasin activated matriptase. Together, our results suggest a role for protease-activated receptor signaling in neural tube closure and identify a local protease network that may trigger Par2 signaling and monitor and regulate epithelial integrity in this context.

Highlights

► Protease-activated receptors (PARs) in surface ectoderm support neural tube closure ► The GPCR effectors Gi and Rac1 in surface ectoderm are also necessary ► Local membrane-tethered serine proteases may activate PARs in this context ► Relevant protease cascades may be positioned to signal epithelial integrity

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7

Present address: Riken Center for Developmental Biology, Kobe 6500047, Japan

8

Present address: National Institutes of Health, Bethesda, MD 20892