Local protease signaling contributes to neural tube closure in the mouse embryo.
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 G(i/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.
Cardiovasular Research Institute, Department of Medicine, University of California, San Francisco, San Francisco, CA 94158, USA.
Eric
E
Camerer
Adrian
A
Barker
Daniel N
DN
Duong
Rajkumar
R
Ganesan
Hiroshi
H
Kataoka
Ivo
I
Cornelissen
Molly R
MR
Darragh
Arif
A
Hussain
Yao-Wu
YW
Zheng
Yoga
Y
Srinivasan
Christopher
C
Brown
Shan-Mei
SM
Xu
Jean B
JB
Regard
Chen-Yong
CY
Lin
Charles S
CS
Craik
Daniel
D
Kirchhofer
Shaun R
SR
Coughlin
D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D002490:Central Nervous System / Q000166:cytology / Q000196:embryology* / Q000378:metabolism*; D047108:Embryonic Development / Q000235:genetics*; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D006801:Humans; D051379:Mice; D008817:Mice, Mutant Strains; D054259:Neural Tube / Q000166:cytology / Q000196:embryology* / Q000378:metabolism*; D009436:Neural Tube Defects / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D010447:Peptide Hydrolases / Q000235:genetics / Q000378:metabolism; D044463:Receptor, PAR-1 / Q000235:genetics / Q000378:metabolism; D044464:Receptor, PAR-2 / Q000235:genetics / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism
D044463:Receptor, PAR-1; D044464:Receptor, PAR-2; D043562:Receptors, G-Protein-Coupled; D010447:Peptide Hydrolases; D019204:GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein