title: Intermediate Progenitors Facilitate Intracortical Progression of Thalamocortical Axons and Interneurons through CXCL12 Chemokine Signaling.
abstract: Glutamatergic principal neurons, GABAergic interneurons and thalamocortical axons (TCAs) are essential elements of the cerebrocortical network. Principal neurons originate locally from radial glia and intermediate progenitors (IPCs), whereas interneurons and TCAs are of extrinsic origin. Little is known how the assembly of these elements is coordinated. C-X-C motif chemokine 12 (CXCL12), which is known to guide axons outside the neural tube and interneurons in the cortex, is expressed in the meninges and IPCs. Using mouse genetics, we dissected the influence of IPC-derived CXCL12 on TCAs and interneurons by showing that Cxcl12 ablation in IPCs, leaving meningeal Cxcl12 intact, attenuates intracortical TCA growth and disrupts tangential interneuron migration in the subventricular zone. In accordance with strong CXCR4 expression in the forming thalamus and TCAs, we identified a CXCR4-dependent growth-promoting effect of CXCL12 on TCAs in thalamus explants. Together, our findings indicate a cell-autonomous role of CXCR4 in promoting TCA growth. We propose that CXCL12 signals from IPCs link cortical neurogenesis to the progression of TCAs and interneurons spatially and temporally. Significance statement: The cerebral cortex exerts higher brain functions including perceptual and emotional processing. Evolutionary expansion of the mammalian cortex is mediated by intermediate progenitors, transient amplifying cells generating cortical excitatory neurons. During the peak period of cortical neurogenesis, migrating precursors of inhibitory interneurons originating in subcortical areas and thalamic axons invade the cortex. Although defects in the assembly of cortical network elements cause neurological and mental disorders, little is known how neurogenesis, interneuron recruitment, and axonal ingrowth are coordinated. We demonstrate that intermediate progenitors release the chemotactic cytokine CXCL12 to promote intracortical interneuron migration and growth of thalamic axons via the cognate receptor CXCR4. This paracrine signal may ensure thalamocortical connectivity and dispersion of inhibitory neurons in the rapidly growing cortex.
authors.affiliation: Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich Schiller University Jena, 07747 Jena, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Abe
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3QX, United Kingdom.
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Molnár
authors.affiliation: Graduate Institute of Oncology, National Taiwan University, Taipei 10002, Taiwan.
authors.forename: Yi-Shiuan
authors.initials: YS
authors.lastname: Tzeng
authors.affiliation: Department of Surgery, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei 10002, Taiwan.
authors.forename: Dar-Ming
authors.identifier: http://orcid.org/0000-0002-9896-5251
authors.initials: DM
authors.lastname: Lai
authors.affiliation: Renal Division, University Hospital Freiburg, 79106 Freiburg, Germany, and BIOSS Centre of Biological Signalling Studies and Institute of Experimental and Clinical Pharmacology and Toxicology, Albert-Ludwigs-University, 79104 Freiburg, Germany.
authors.forename: Sebastian J
authors.initials: SJ
authors.lastname: Arnold
authors.affiliation: Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich Schiller University Jena, 07747 Jena, Germany, Ralf.Stumm@med.uni-jena.de.
authors.forename: Ralf
authors.identifier: http://orcid.org/0000-0002-9458-5526
authors.initials: R
authors.lastname: Stumm
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism; D002540:Cerebral Cortex / Q000166:cytology* / Q000196:embryology; D054377:Chemokine CXCL12 / Q000235:genetics / Q000378:metabolism*; D004622:Embryo, Mammalian; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D007382:Intermediate Filaments / Q000378:metabolism; D007395:Interneurons / Q000502:physiology*; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins; D009434:Neural Pathways / Q000502:physiology; D009924:Organ Culture Techniques; D054387:Receptors, CXCR / Q000235:genetics / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D013234:Stem Cells / Q000502:physiology*; D013788:Thalamus / Q000166:cytology* / Q000196:embryology
chemical_list: C514936:CXCR4 protein, mouse; D054377:Chemokine CXCL12; C501897:Cmkor1 protein, mouse; D008164:Luminescent Proteins; D009419:Nerve Tissue Proteins; D054387:Receptors, CXCR; D019718:Receptors, CXCR4
keywords: CXCL12/CXCR4; cortical development; intermediate/basal progenitors; interneuron; thalamocortical axons; thalamus