title: NrCAM deletion causes topographic mistargeting of thalamocortical axons to the visual cortex and disrupts visual acuity.
abstract: NrCAM is a neural cell adhesion molecule of the L1 family that has been linked to autism spectrum disorders, a disease spectrum in which abnormal thalamocortical connectivity may contribute to visual processing defects. Here we show that NrCAM interaction with neuropilin-2 (Npn-2) is critical for semaphorin 3F (Sema3F)-induced guidance of thalamocortical axon subpopulations at the ventral telencephalon (VTe), an intermediate target for thalamic axon sorting. Genetic deletion of NrCAM or Npn-2 caused contingents of embryonic thalamic axons to misproject caudally in the VTe. The resultant thalamocortical map of NrCAM-null mutants showed striking mistargeting of motor and somatosensory thalamic axon contingents to the primary visual cortex, but retinogeniculate targeting and segregation were normal. NrCAM formed a molecular complex with Npn-2 in brain and neural cells, and was required for Sema3F-induced growth cone collapse in thalamic neuron cultures, consistent with a vital function for NrCAM in Sema3F-induced axon repulsion. NrCAM-null mice displayed reduced responses to visual evoked potentials recorded from layer IV in the binocular zone of primary visual cortex (V1), particularly when evoked from the ipsilateral eye, indicating abnormal visual acuity and ocularity. These results demonstrate that NrCAM is required for normal maturation of cortical visual acuity, and suggest that the aberrant projection of thalamic motor and somatosensory axons to the visual cortex in NrCAM-null mutant mice impairs cortical functions.
authors.affiliation: Department of Biochemistry and Biophysics, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
authors.forename: Galina P
authors.initials: GP
authors.lastname: Demyanenko
authors.forename: Thorfinn T
authors.initials: TT
authors.lastname: Riday
authors.forename: Tracy S
authors.initials: TS
authors.lastname: Tran
authors.forename: Jasbir
authors.initials: J
authors.lastname: Dalal
authors.forename: Eli P
authors.initials: EP
authors.lastname: Darnell
authors.forename: Leann H
authors.initials: LH
authors.lastname: Brennaman
authors.forename: Takeshi
authors.initials: T
authors.lastname: Sakurai
authors.forename: Martin
authors.initials: M
authors.lastname: Grumet
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Philpot
authors.forename: Patricia F
authors.initials: PF
authors.lastname: Maness
mesh_terms: D000818:Animals; D001369:Axons / Q000502:physiology*; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000502:physiology*; D005074:Evoked Potentials, Visual; D005260:Female; D020439:Growth Cones / Q000502:physiology; D008297:Male; D008565:Membrane Proteins / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009044:Motor Cortex / Q000196:embryology / Q000254:growth & development / Q000648:ultrastructure*; D009419:Nerve Tissue Proteins / Q000502:physiology; D039943:Neuropilin-2 / Q000235:genetics / Q000502:physiology; D013003:Somatosensory Cortex / Q000196:embryology / Q000254:growth & development / Q000648:ultrastructure*; D013788:Thalamus / Q000196:embryology / Q000254:growth & development / Q000648:ultrastructure*; D014792:Visual Acuity; D014793:Visual Cortex / Q000196:embryology / Q000254:growth & development / Q000648:ultrastructure*
chemical_list: D015815:Cell Adhesion Molecules; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D039943:Neuropilin-2; C491151:Nrcam protein, mouse; C491229:Sema3f protein, mouse