title: Transcriptional Control of Synaptic Remodeling through Regulated Expression of an Immunoglobulin Superfamily Protein.
abstract: Neural circuits are actively remodeled during brain development, but the molecular mechanisms that trigger circuit refinement are poorly understood. Here, we describe a transcriptional program in C. elegans that regulates expression of an Ig domain protein, OIG-1, to control the timing of synaptic remodeling. DD GABAergic neurons reverse polarity during larval development by exchanging the locations of pre- and postsynaptic components. In newly born larvae, DDs receive cholinergic inputs in the dorsal nerve cord. These inputs are switched to the ventral side by the end of the first larval (L1) stage. VD class GABAergic neurons are generated in the late L1 and are postsynaptic to cholinergic neurons in the dorsal nerve cord but do not remodel. We investigated remodeling of the postsynaptic apparatus in DD and VD neurons using targeted expression of the acetylcholine receptor (AChR) subunit, ACR-12::GFP. We determined that OIG-1 antagonizes the relocation of ACR-12 from the dorsal side in L1 DD neurons. During the L1/L2 transition, OIG-1 is downregulated in DD neurons by the transcription factor IRX-1/Iroquois, allowing the repositioning of synaptic inputs to the ventral side. In VD class neurons, which normally do not remodel, the transcription factor UNC-55/COUP-TF turns off IRX-1, thus maintaining high levels of OIG-1 to block the removal of dorsally located ACR-12 receptors. OIG-1 is secreted from GABA neurons, but its anti-plasticity function is cell autonomous and may not require secretion. Our study provides a novel mechanism by which synaptic remodeling is set in motion through regulated expression of an Ig domain protein.
authors.affiliation: Neuroscience Graduate Program, Vanderbilt International Scholar Program, Vanderbilt University, 465 21(st) Avenue South, Nashville, TN 37240-7935, USA.
authors.forename: Siwei
authors.initials: S
authors.lastname: He
authors.affiliation: Department of Neurobiology, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605, USA.
authors.forename: Alison
authors.initials: A
authors.lastname: Philbrook
authors.affiliation: Department of Cell and Developmental Biology, Vanderbilt University, 465 21(st) Avenue South, Nashville, TN 37240-7935, USA.
authors.forename: Rebecca
authors.initials: R
authors.lastname: McWhirter
authors.affiliation: Department of Physiology and Biophysics, Boston University Medical Campus, 700 Albany Street, Boston, MA 02118, USA.
authors.forename: Christopher V
authors.initials: CV
authors.lastname: Gabel
authors.affiliation: Department of Physiology and Biophysics, Boston University Medical Campus, 700 Albany Street, Boston, MA 02118, USA.
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Taub
authors.affiliation: Department of Cell and Developmental Biology, Vanderbilt University, 465 21(st) Avenue South, Nashville, TN 37240-7935, USA.
authors.forename: Maximilian H
authors.initials: MH
authors.lastname: Carter
authors.affiliation: Department of Cell and Developmental Biology, Vanderbilt University, 465 21(st) Avenue South, Nashville, TN 37240-7935, USA.
authors.forename: Isabella M
authors.initials: IM
authors.lastname: Hanna
authors.affiliation: Department of Neurobiology, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605, USA. Electronic address: michael.francis@umassmed.edu.
authors.forename: Michael M
authors.initials: MM
authors.lastname: Francis
authors.affiliation: Neuroscience Graduate Program, Vanderbilt International Scholar Program, Vanderbilt University, 465 21(st) Avenue South, Nashville, TN 37240-7935, USA; Department of Cell and Developmental Biology, Vanderbilt University, 465 21(st) Avenue South, Nashville, TN 37240-7935, USA. Electronic address: david.miller@vanderbilt.edu.
authors.forename: David M
authors.initials: DM
authors.lastname: Miller
mesh_terms: D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D017173:Caenorhabditis elegans; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D059330:GABAergic Neurons / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D005786:Gene Expression Regulation; D007136:Immunoglobulins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D009046:Motor Neurons / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D011950:Receptors, Cholinergic / Q000378:metabolism; D013569:Synapses / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D029742:Caenorhabditis elegans Proteins; D007136:Immunoglobulins; D009419:Nerve Tissue Proteins; C000599895:OIG-1 protein, C elegans; D011950:Receptors, Cholinergic; D014157:Transcription Factors; D000109:Acetylcholine