Deficits in microRNA-mediated Cxcr4/Cxcl12 signaling in neurodevelopmental deficits in a 22q11 deletion syndrome mouse model

Toritsuka, Michihiro; Kimoto, Sohei; Muraki, Kazue; Landek-Salgado, Melissa A.; Yoshida, Atsuhiro; Yamamoto, Norio; Horiuchi, Yasue; Hiyama, Hideki; Tajinda, Katsunori; Ni, Keni; Illingworth, Elizabeth; Iwamoto, Takashi; Kishimoto, Toshifumi; Sawa, Akira; Tanigaki, Kenji

doi:10.1073/pnas.1312661110

Cited by 68 publications

(57 citation statements)

References 31 publications

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“…4D). Taken together with the recent results showing functional defects of CXCR4 signaling in the brain of the LgDel and Df1 mouse models (Meechan et al, 2012;Toritsuka et al, 2013), our study underlines the possibility of a pivotal role for the SDF1/CXCR4 axis in DGS etiology.…”

Section: Resultssupporting

confidence: 83%

“…Despite progress in the identification of Tbx1 targets, the molecular mechanisms involved in pharyngeal NC development that could account for DGS etiology have not been completely elucidated. Interestingly, signaling by CXCR4, a receptor for the chemokine stromal derived factor 1 (SDF1, also named CXCL12), is deficient in brain cortical interneurons of mouse DGS models, resulting in their abnormal migration, probably accounting for the mental disorders observed in DGS patients (Meechan et al, 2012;Toritsuka et al, 2013). Loss of Cxcr4 or Sdf1 in mouse causes cardiac anomalies similar to those observed in DGS (Ma et al, 1998) and disruption of SDF1/ CXCR4 signaling in chick demonstrated that these cardiac defects result from abnormal migration of cardiac NCs (Escot et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

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Disruption of CXCR4 signaling in pharyngeal neural crest cells causes DiGeorge syndrome-like malformations

et al. 2016

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DiGeorge syndrome (DGS) is a congenital disease causing cardiac outflow tract anomalies, craniofacial dysmorphogenesis, thymus hypoplasia, and mental disorders. It results from defective development of neural crest cells (NCs) that colonize the pharyngeal arches and contribute to lower jaw, neck and heart tissues. Although TBX1 has been identified as the main gene accounting for the defects observed in human patients and mouse models, the molecular mechanisms underlying DGS etiology are poorly identified. The recent demonstrations that the SDF1/CXCR4 axis is implicated in NC chemotactic guidance and impaired in cortical interneurons of mouse DGS models prompted us to search for genetic interactions between Tbx1, Sdf1 (Cxcl12) and Cxcr4 in pharyngeal NCs and to investigate the effect of altering CXCR4 signaling on the ontogeny of their derivatives, which are affected in DGS. Here, we provide evidence that Cxcr4 and Sdf1 are genetically downstream of Tbx1 during pharyngeal NC development and that reduction of CXCR4 signaling causes misrouting of pharyngeal NCs in chick and dramatic morphological alterations in the mandibular skeleton, thymus and cranial sensory ganglia. Our results therefore support the possibility of a pivotal role for the SDF1/CXCR4 axis in DGS etiology.

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Section: Resultssupporting

confidence: 83%

Section: Introductionmentioning

confidence: 99%

Disruption of CXCR4 signaling in pharyngeal neural crest cells causes DiGeorge syndrome-like malformations

et al. 2016

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“…Finally, we lack a biophysical description of chemokine diffusion and cellular chemokine perception. Given the important role of chemokine signaling in immune system disorders (Zlotnik and Yoshie, 2012) and cancer (Dorsam and Gutkind, 2007;Zlotnik et al, 2011), and its emerging role in psychiatric disorders such as schizophrenia (Meechan et al, 2012;Toritsuka et al, 2013), an understanding of these issues is crucial. With advances in light microscopy and quantitative measurements, such fundamental questions should become addressable in the future.…”

Section: Resultsmentioning

confidence: 99%

Chemokine signaling in development and disease

2014

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Chemokines are a group of small, secreted molecules that signal through G protein-coupled receptors to promote cell survival and proliferation and to provide directional guidance to migrating cells. CXCL12 is one of the most evolutionary conserved chemokines and signals through the chemokine receptor CXCR4 to guide cell migration during embryogenesis, immune cell trafficking and cancer metastasis. Here and in the accompanying poster, we provide an overview of chemokine signaling, focusing on CXCL12, and we highlight some of the different chemokine-dependent strategies used to guide migrating cells.

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“…Defective CXCR4 regulation has recently been implicated in the perturbed intracortical migration of GABAergic interneurons in genetic schizophrenia models (Meechan et al, 2012;Toritsuka et al, 2013). Cortical interneurons originate in the ganglionic eminences in the ventral telencephalon (Anderson et al, 1997;Marín and Rubenstein, 2001;Hernández-Miranda et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

CXCR7 prevents excessive CXCL12-mediated downregulation of CXCR4 in migrating cortical interneurons

et al. 2014

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The CXCL12/CXCR4 signaling pathway is involved in the development of numerous neuronal and non-neuronal structures. Recent work established that the atypical second CXCL12 receptor, CXCR7, is essential for the proper migration of interneuron precursors in the developing cerebral cortex. Two CXCR7-mediated functions were proposed in this process: direct modulation of β-arrestin-mediated signaling cascades and CXCL12 scavenging to regulate local chemokine availability and ensure responsiveness of the CXCL12/ CXCR4 pathway in interneurons. Neither of these functions has been proven in the embryonic brain. Here, we demonstrate that migrating interneurons efficiently sequester CXCL12 through CXCR7. CXCR7 ablation causes excessive phosphorylation and downregulation of CXCR4 throughout the cortex in mice expressing CXCL12, but not in CXCL12-deficient animals. Cxcl12 −/− mice lack activated CXCR4 in embryonic brain lysates and display a similar interneuron positioning defect as Cxcr4−/− and Cxcl12 −/−;Cxcr7 −/− animals. Thus, CXCL12 is the only CXCR4-activating ligand in the embryonic brain and deletion of one of the CXCL12 receptors is sufficient to generate a migration phenotype that corresponds to the CXCL12-deficient pathway. Our findings imply that interfering with the CXCL12-scavenging activity of CXCR7 causes loss of CXCR4 function as a consequence of excessive CXCL12-mediated CXCR4 activation and degradation.

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Deficits in microRNA-mediated Cxcr4/Cxcl12 signaling in neurodevelopmental deficits in a 22q11 deletion syndrome mouse model

Cited by 68 publications

References 31 publications

Disruption of CXCR4 signaling in pharyngeal neural crest cells causes DiGeorge syndrome-like malformations

Disruption of CXCR4 signaling in pharyngeal neural crest cells causes DiGeorge syndrome-like malformations

Chemokine signaling in development and disease

CXCR7 prevents excessive CXCL12-mediated downregulation of CXCR4 in migrating cortical interneurons

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