title: SARA regulates neuronal migration during neocortical development through L1 trafficking.
abstract: Emerging evidence suggests that endocytic trafficking of adhesion proteins plays a crucial role in neuronal migration during neocortical development. However, molecular insights into these processes remain elusive. Here, we study the early endosomal protein Smad anchor for receptor activation (SARA) in the developing mouse brain. SARA is enriched at the apical endfeet of radial glia of the neocortex. Although SARA knockdown did not lead to detectable neurogenic phenotypes, SARA-suppressed neurons exhibited impaired orientation and migration across the intermediate zone. Mechanistically, we show that SARA knockdown neurons exhibit increased surface expression of the L1 cell adhesion molecule. Neurons ectopically expressing L1 phenocopy the migration and orientation defects caused by SARA knockdown and display increased contact with neighboring neurites. L1 knockdown effectively rescues SARA suppression-induced phenotypes. SARA knockdown neurons eventually overcome their migration defect and enter later into the cortical plate. Nevertheless, these neurons localize at more superficial cortical layers than their control counterparts. These results suggest that SARA regulates the orientation, multipolar-to-bipolar transition and the positioning of cortical neurons via modulating surface L1 expression.
authors.affiliation: INIMEC, Instituto de Investigación Médica Mercedes y Martín Ferreyra, CONICET, Universidad Nacional de Córdoba UNC, Friuli 2434-5016, Córdoba, Argentina DFG-Research Center for Regenerative Therapies, Cluster of Excellence, TU-Dresden, Fetscherstrasse 105, Dresden 01307, Germany.
authors.forename: Iván
authors.initials: I
authors.lastname: Mestres
authors.affiliation: Department of Ophthalmology, Dyson Vision Research Institute, Weill Medical College of Cornell University, New York, NY 10065, USA.
authors.forename: Jen-Zen
authors.initials: JZ
authors.lastname: Chuang
authors.affiliation: DFG-Research Center for Regenerative Therapies, Cluster of Excellence, TU-Dresden, Fetscherstrasse 105, Dresden 01307, Germany.
authors.forename: Federico
authors.initials: F
authors.lastname: Calegari
authors.affiliation: INIMEC, Instituto de Investigación Médica Mercedes y Martín Ferreyra, CONICET, Universidad Nacional de Córdoba UNC, Friuli 2434-5016, Córdoba, Argentina Instituto Universitario Ciencias Biomédicas Córdoba (IUCBC), Córdoba 5016, Argentina.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Conde
authors.affiliation: Department of Ophthalmology, Dyson Vision Research Institute, Weill Medical College of Cornell University, New York, NY 10065, USA Departments of Cell and Developmental Biology, Weill Medical College of Cornell University, New York, NY 10065, USA chsung@med.cornell.edu.
authors.forename: Ching-Hwa
authors.identifier: 0000-0002-3468-5867
authors.initials: CH
authors.lastname: Sung
mesh_terms: D000818:Animals; D001921:Brain / Q000166:cytology / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002465:Cell Movement / Q000235:genetics / Q000502:physiology; D018274:Electroporation; D005260:Female; D019204:GTP-Binding Proteins; D006801:Humans; D015151:Immunoblotting; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D019579:Neocortex / Q000166:cytology / Q000378:metabolism*; D039842:Neural Cell Adhesion Molecule L1 / Q000235:genetics / Q000378:metabolism*; D055495:Neurogenesis / Q000235:genetics / Q000502:physiology; D009474:Neurons / Q000378:metabolism*; D011247:Pregnancy; D021381:Protein Transport / Q000235:genetics / Q000502:physiology; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D039842:Neural Cell Adhesion Molecule L1; C491124:SARA protein, mouse; C116420:ZFYVE16 protein, human; D012697:Serine Endopeptidases; D019204:GTP-Binding Proteins
keywords: Adhesion; Cortical neuron migration; Endosomal trafficking; L1CAM; SARA; Zfyve9