GPR56 regulates pial basement membrane integrity and cortical lamination.
GPR56 is a member of the family of adhesion G-protein-coupled receptors that have a large extracellular region containing a GPS (G-protein proteolytic site) domain. Loss-of-function mutations in the GPR56 gene cause a specific human brain malformation called bilateral frontoparietal polymicrogyria (BFPP). BFPP is a radiological diagnosis and its histopathology remains unclear. This study demonstrates that loss of the mouse Gpr56 gene leads to neuronal ectopia in the cerebral cortex, a cobblestone-like cortical malformation. There are four crucial events in the development of cobblestone cortex, namely defective pial basement membrane (BM), abnormal anchorage of radial glial endfeet, mislocalized Cajal-Retzius cells, and neuronal overmigration. By detailed time course analysis, we reveal that the leading causal events are likely the breaches in the pial BM. We show further that GPR56 is present in abundance in radial glial endfeet. Furthermore, a putative ligand of GPR56 is localized in the marginal zone or overlying extracellular matrix. These observations provide compelling evidence that GPR56 functions in regulating pial BM integrity during cortical development.
Division of Newborn Medicine, Department of Medicine, Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts 02115, USA.
Shihong
S
Li
Zhaohui
Z
Jin
Samir
S
Koirala
Lihong
L
Bu
Lei
L
Xu
Richard O
RO
Hynes
Christopher A
CA
Walsh
Gabriel
G
Corfas
Xianhua
X
Piao
D018528:ATP-Binding Cassette Transporters; D000818:Animals; D000831:Animals, Newborn; D001425:Bacterial Outer Membrane Proteins; D001485:Basement Membrane / Q000378:metabolism*; D001973:Bromodeoxyuridine / Q000378:metabolism; D002465:Cell Movement / Q000235:genetics; D002540:Cerebral Cortex / Q000002:abnormalities / Q000166:cytology*; D004622:Embryo, Mammalian; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D034882:Lamins / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation / Q000502:physiology; D009457:Neuroglia / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D010841:Pia Mater / Q000166:cytology*; D043562:Receptors, G-Protein-Coupled / Q000172:deficiency / Q000502:physiology*; D013234:Stem Cells / Q000378:metabolism; D014404:Tubulin / Q000378:metabolism
D018528:ATP-Binding Cassette Transporters; D001425:Bacterial Outer Membrane Proteins; D001973:Bromodeoxyuridine; D034882:Lamins; D043562:Receptors, G-Protein-Coupled; D014404:Tubulin; C524781:Adgrg1 protein, mouse; C093955:PrtF protein, bacteria; C462941:beta3 tubulin, mouse