title: Sonic hedgehog expression in corticofugal projection neurons directs cortical microcircuit formation.
abstract: The precise connectivity of inputs and outputs is critical for cerebral cortex function; however, the cellular mechanisms that establish these connections are poorly understood. Here, we show that the secreted molecule Sonic Hedgehog (Shh) is involved in synapse formation of a specific cortical circuit. Shh is expressed in layer V corticofugal projection neurons and the Shh receptor, Brother of CDO (Boc), is expressed in local and callosal projection neurons of layer II/III that synapse onto the subcortical projection neurons. Layer V neurons of mice lacking functional Shh exhibit decreased synapses. Conversely, the loss of functional Boc leads to a reduction in the strength of synaptic connections onto layer Vb, but not layer II/III, pyramidal neurons. These results demonstrate that Shh is expressed in postsynaptic target cells while Boc is expressed in a complementary population of presynaptic input neurons, and they function to guide the formation of cortical microcircuitry.
authors.affiliation: Eli and Edythe Broad Institute of Regeneration Medicine and Stem Cell Research, University of California-San Francisco, San Francisco, CA 94143, USA. harwellc@stemcell.ucsf.edu
authors.forename: Corey C
authors.initials: CC
authors.lastname: Harwell
authors.forename: Philip R L
authors.initials: PR
authors.lastname: Parker
authors.forename: Steven M
authors.initials: SM
authors.lastname: Gee
authors.forename: Ami
authors.initials: A
authors.lastname: Okada
authors.forename: Susan K
authors.initials: SK
authors.lastname: McConnell
authors.forename: Anatol C
authors.initials: AC
authors.lastname: Kreitzer
authors.forename: Arnold R
authors.initials: AR
authors.lastname: Kriegstein
mesh_terms: D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D002540:Cerebral Cortex / Q000166:cytology* / Q000254:growth & development; D000075402:Channelrhodopsins; D003337:Corpus Callosum / Q000166:cytology / Q000254:growth & development; D004268:DNA-Binding Proteins / Q000378:metabolism; D049229:Dendritic Spines / Q000378:metabolism / Q000502:physiology; D004558:Electric Stimulation; D018274:Electroporation / Q000379:methods; D005464:Fluorobenzenes / Q000378:metabolism; D007839:Functional Laterality / Q000235:genetics; D005663:Furans / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000235:genetics / Q000502:physiology*; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D007074:Immunoglobulin G / Q000235:genetics / Q000378:metabolism; D066298:In Vitro Techniques; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D036961:Matrix Attachment Region Binding Proteins / Q000378:metabolism; D008564:Membrane Potentials / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009415:Nerve Net / Q000166:cytology / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism* / Q000648:ultrastructure; D009687:Nuclear Proteins / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D011712:Pyramidal Tracts / Q000502:physiology*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D016622:Silver Staining / Q000379:methods; D013266:Stilbamidines / Q000378:metabolism; D013569:Synapses / Q000378:metabolism / Q000648:ultrastructure; D016708:Synaptophysin / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases; D005680:gamma-Aminobutyric Acid / Q000378:metabolism; D000070584:Tripartite Motif Proteins
chemical_list: D000075402:Channelrhodopsins; D004268:DNA-Binding Proteins; D005464:Fluorobenzenes; D005663:Furans; D053823:Hedgehog Proteins; D007074:Immunoglobulin G; D008164:Luminescent Proteins; D036961:Matrix Attachment Region Binding Proteins; D009687:Nuclear Proteins; D010751:Phosphopyruvate Hydratase; D034741:RNA, Small Interfering; D011956:Receptors, Cell Surface; D012097:Repressor Proteins; D013266:Stilbamidines; D016708:Synaptophysin; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases; D005680:gamma-Aminobutyric Acid; C049774:2-hydroxy-4,4'-diamidinostilbene, methanesulfonate salt; C421259:3,4-difluorobenzyloxy-5,5-dimethyl-4-(4-methylsulfonylphenyl)-(5H)-furan-2-one; C511143:Bcl11b protein, mouse; C510745:Boc protein, mouse; C501473:SATB2 protein, mouse; C465570:Shh protein, mouse; C489296:Trim27 protein, mouse; D000070584:Tripartite Motif Proteins