GPR56 Regulates Pial Basement Membrane Integrity and Cortical Lamination

Li, Shihong; Jin, Zhaohui; Koirala, Samir; Bu, Le; Xu, Lei; Hynes, Richard O.; Walsh, Christopher A.; Corfas, Gabriel; Piao, Xiangshu

doi:10.1523/jneurosci.0853-08.2008

Cited by 211 publications

(262 citation statements)

References 36 publications

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“…Furthermore, stimulation of GPR56 in cultured neural precursor cells with an activating antibody results in decreased cellular migration (5). These observations in cultured cells are consistent with in vivo studies demonstrating that GPR56 knockout mice exhibit a cobblestone-like malformation of the cerebral cortex resulting from overmigration of neural precursor cells (7). These findings suggest a model in which GPR56 expressed in neural precursor cells plays a key role in sensing an extracellular signal that cues the cells to stop and differentiate.…”

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confidence: 87%

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The N Terminus of the Adhesion G Protein-coupled Receptor GPR56 Controls Receptor Signaling Activity

Paavola

Stephenson

Ritter

et al. 2011

Journal of Biological Chemistry

156

201

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GPR56 is an adhesion G protein-coupled receptor that plays a key role in cortical development. Mutations to GPR56 in humans cause malformations of the cerebral cortex, but little is known about the normal function of the receptor. We found that the large N terminus (NT) of GPR56 is cleaved from the rest of the receptor during processing but remains non-covalently associated with the seven-transmembrane region of the receptor, as indicated by coimmunoprecipitation of the two GPR56 fragments from both transfected cells and native tissue. We also found that truncation of the GPR56 NT results in constitutive activation of receptor signaling, as revealed by increased GPR56-stimulated signaling upon transfection of HEK-293 cells with truncated GPR56, greatly enhanced binding of ␤-arrestins by truncated GPR56 relative to the full-length receptor, extensive ubiquitination of truncated GPR56, and cytotoxicity induced by truncated GPR56 that could be rescued by cotransfection of cells with ␤-arrestin 2. Furthermore, we found that the GPR56 NT is capable of homophilic trans-trans interactions that enhance receptor signaling activity. On the basis of these findings, we suggest a model of receptor activation in which the large N terminus of GPR56 constrains receptor activity but N-terminal interactions (GPR56 NT with an extracellular ligand and/or GPR56 NT homophilic trans-trans associations) can remove this inhibitory influence of the N terminus to activate receptor signaling.During the development of the cerebral cortex, neuronal precursors proliferate in the ventricular and subventricular zones that line the cerebral cavity and then migrate outward to make connections with other neurons. Given the billions of cells involved and the requirements for temporal and spatial precision, it is perhaps not surprising that many different types of problems can arise during this process. Abnormalities in cortical development can lead to a range of distinct neurodevelopmental disorders, some of which are caused by mutations to a single gene. For example, bilateral frontoparietal polymicrogyria is a condition in which patients exhibit profound cognitive abnormalities and seizures because of disordered cortical connectivity in the frontoparietal area. Bilateral frontoparietal polymicrogyria is an autosomal recessive syndrome that results from mutations in the orphan receptor GPR56 (1). Thus, insights into the natural function of GPR56 might shed light on the specific pathology underlying bilateral frontoparietal polymicrogyria and also lead to new insights about the fundamental mechanisms controlling cortical development.GPR56 is a member of the adhesion family of G proteincoupled receptors (GPCRs) 2 , which are characterized by extremely large extracellular N termini (NT) exhibiting homology to adhesion proteins (2). There are approximately 30 adhesion GPCRs, all of which are still considered to be orphan receptors. Almost all members of the adhesion GPCR family possess an N-terminal region known as a "GPCR proteolytic site" or GPS dom...

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supporting

confidence: 87%

“…GPR56 regulates the migration of neural precursor cells in vitro (5) and in vivo (7,26), but little is known about the mechanism of activation for GPR56. On the basis of our findings here, we propose that removal of the GPR56 N terminus can result in receptor activation.…”

Section: Discussionmentioning

confidence: 99%

The N Terminus of the Adhesion G Protein-coupled Receptor GPR56 Controls Receptor Signaling Activity

Paavola

Stephenson

Ritter

et al. 2011

Journal of Biological Chemistry

156

201

View full text Add to dashboard Cite

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“…The demonstration, in TUBB2B mutation, of focal breaches in the basement membrane and neuronal overmigration leading to a polymicrogyra-like pattern led to the suggestion that radial glial cells play a role in development of the pial basement membrane, as indicated in GPR56 mutation (Li et al 2008). However, it may be a bit more complicated than that.…”

Section: Overmigration Syndromesmentioning

confidence: 99%

“…However, it may be a bit more complicated than that. First, in several mutations associated with cortical dysplasia the pial basement membrane appears to develop normally; breaches develop later (Blackshear et al 1997;Hu et al 2007;Li et al 2008), suggesting that defects arise as a result of instability of the basement membrane during remodelling and brain growth. Secondly, it appears that the basement membrane per se may influence cortical development (Zarbalis et al 2007;Radakovits et al 2009;Siegenthaler et al 2009).…”

Section: Overmigration Syndromesmentioning

confidence: 99%

Abnormal development of the human cerebral cortex

Squier

Jansen

2010

Journal of Anatomy

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This review presents an overview of human cortical malformation based on the insights gained from examination of human fetal brains. Examination at early stages of fetal brain development allows the identification of the specific pathways which are disrupted in human cortical malformation. Detailed examination of human fetal brains in parallel with studies of genetics and animal models is leading to new concepts of cortical malformations. Here we review a range of human cortical malformations based on a simple classification according to the developmental process thought to be disrupted: neuroblast proliferation, undermigration, overmigration, cortical maturation and destructive lesions. A single case example of a dated intrauterine injury illustrates the spectrum of malformations which may result at a single period in development. The recommended methods of examination of human fetal brain are described together with some of their pitfalls. Detailed neuropathological observations indicate the need for caution in the classification of malformations; radiological findings and pathology of the mature brain do not reflect the specific disruptive pathways of cortical malformations. While many insults may lead to the same pattern of malformation, a single insult can lead to multiple patterns of malformation. Our detailed studies of the human fetal brain suggest that the interface between the meninges and the radial glial end feet may be an intriguing new focus of interest in understanding cortical development.

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“…Many GPCR agonists, such as S1P, LPA, endothelin-1 (ET1), and cannabinoids, are reported to enhance proliferation of neural progenitor cells through extracellular signal-regulated kinase (ERK) phosphorylation (Estivill-Torrú s et al, 2008;Harada et al, 2004;Jiang et al, 2005;Mizugishi et al, 2005;Morishita et al, 2007;Palazuelos et al, 2006;Shinohara et al, 2004). Loss of Ga12 and Ga13 or Gpr56 results in overmigration of neurons, and Cxcr4 and Sdf1 are required for normal cerebellar neuron migration (Li et al, 2008;Ma et al, 1998;Moers et al, 2008;Zou et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

Neural tube defects and impaired neural progenitor cell proliferation in Gβ1‐deficient mice

Okae

Iwakura

2010

Developmental Dynamics

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Heterotrimeric G proteins are well known for their roles in signal transduction downstream of G protein–coupled receptors (GPCRs), and both Gα subunits and tightly associated Gβγ subunits regulate downstream effector molecules. Compared to Gα subunits, the physiological roles of individual Gβ and Gγ subunits are poorly understood. In this study, we generated mice deficient in the Gβ1 gene and found that Gβ1 is required for neural tube closure, neural progenitor cell proliferation, and neonatal development. About 40% Gβ1−/− embryos developed neural tube defects (NTDs) and abnormal actin organization was observed in the basal side of neuroepithelium. In addition, Gβ1−/− embryos without NTDs showed microencephaly and died within 2 days after birth. GPCR agonist‐induced ERK phosphorylation, cell proliferation, and cell spreading, which were all found to be regulated by Gαi and Gβγ signaling, were abnormal in Gβ1−/− neural progenitor cells. These data indicate that Gβ1 is required for normal embryonic neurogenesis. Developmental Dynamics 239:1089–1101, 2010. © 2010 Wiley‐Liss, Inc.

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GPR56 Regulates Pial Basement Membrane Integrity and Cortical Lamination

Cited by 211 publications

References 36 publications

The N Terminus of the Adhesion G Protein-coupled Receptor GPR56 Controls Receptor Signaling Activity

The N Terminus of the Adhesion G Protein-coupled Receptor GPR56 Controls Receptor Signaling Activity

Abnormal development of the human cerebral cortex

Neural tube defects and impaired neural progenitor cell proliferation in Gβ1‐deficient mice

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