title: Zic2-dependent axon midline avoidance controls the formation of major ipsilateral tracts in the CNS.
abstract: In bilaterally symmetric organisms, interhemispheric communication is essential for sensory processing and motor coordination. The mechanisms that govern axon midline crossing during development have been well studied, particularly at the spinal cord. However, the molecular program that determines axonal ipsilaterality remains poorly understood. Here, we demonstrate that ipsilateral neurons whose axons grow in close proximity to the midline, such as the ascending dorsospinal tracts and the rostromedial thalamocortical projection, avoid midline crossing because they transiently activate the transcription factor Zic2. In contrast, uncrossed neurons whose axons never approach the midline control axonal laterality by Zic2-independent mechanisms. Zic2 induces EphA4 expression in dorsospinal neurons to prevent midline crossing while Robo3 is downregulated to ensure that axons enter the dorsal tracts instead of growing ventrally. Together with previous reports, our data reveal a critical role for Zic2 as a determinant of axon midline avoidance in the CNS across species and pathways.
authors.affiliation: Instituto de Neurociencias de Alicante (Consejo Superior de Investigaciones Científicas-Universidad Miguel Hernández, CSIC-UMH), Campus San Juan, Av. Ramón y Cajal s/n, Alicante 03550, Spain.
authors.forename: Augusto
authors.initials: A
authors.lastname: Escalante
authors.affiliation: Instituto de Neurociencias de Alicante (Consejo Superior de Investigaciones Científicas-Universidad Miguel Hernández, CSIC-UMH), Campus San Juan, Av. Ramón y Cajal s/n, Alicante 03550, Spain.
authors.forename: Blanca
authors.initials: B
authors.lastname: Murillo
authors.affiliation: Instituto de Neurociencias de Alicante (Consejo Superior de Investigaciones Científicas-Universidad Miguel Hernández, CSIC-UMH), Campus San Juan, Av. Ramón y Cajal s/n, Alicante 03550, Spain.
authors.forename: Cruz
authors.initials: C
authors.lastname: Morenilla-Palao
authors.affiliation: Department of Medical Neurobiology, IMRIC, Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
authors.forename: Avihu
authors.initials: A
authors.lastname: Klar
authors.affiliation: Instituto de Neurociencias de Alicante (Consejo Superior de Investigaciones Científicas-Universidad Miguel Hernández, CSIC-UMH), Campus San Juan, Av. Ramón y Cajal s/n, Alicante 03550, Spain. Electronic address: e.herrera@umh.es.
authors.forename: Eloísa
authors.initials: E
authors.lastname: Herrera
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism; D058948:Cell Tracking; D002490:Central Nervous System / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D007395:Interneurons / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009434:Neural Pathways / Q000166:cytology / Q000254:growth & development / Q000378:metabolism; D020671:Posterior Horn Cells / Q000166:cytology / Q000254:growth & development / Q000378:metabolism*; D036122:Receptor, EphA4 / Q000378:metabolism; D011956:Receptors, Cell Surface; D013116:Spinal Cord / Q000166:cytology / Q000254:growth & development / Q000378:metabolism*; D013788:Thalamus / Q000166:cytology / Q000254:growth & development / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D000097905:Roundabout Proteins
chemical_list: D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D036122:Receptor, EphA4; D011956:Receptors, Cell Surface; D014157:Transcription Factors; C118348:Robo3 protein, mouse; D000097905:Roundabout Proteins; C491811:Zic2 protein, mouse