title: ϒ-secretase and LARG mediate distinct RGMa activities to control appropriate layer targeting within the optic tectum.
abstract: While a great deal of progress has been made in understanding the molecular mechanisms that regulate retino-tectal mapping, the determinants that target retinal projections to specific layers of the optic tectum remain elusive. Here we show that two independent RGMa-peptides, C- and N-RGMa, activate two distinct intracellular pathways to regulate axonal growth. C-RGMa utilizes a Leukemia-associated RhoGEF (LARG)/Rho/Rock pathway to inhibit axonal growth. N-RGMa on the other hand relies on ϒ-secretase cleavage of the intracellular portion of Neogenin to generate an intracellular domain (NeICD) that uses LIM-only protein 4 (LMO4) to block growth. In the developing tectum (E18), overexpression of C-RGMa and dominant-negative LARG (LARG-PDZ) induced overshoots in the superficial tectal layer but not in deeper tectal layers. In younger embryos (E12), C-RGMa and LARG-PDZ prevented ectopic projections toward deeper tectal layers, indicating that C-RGMa may act as a barrier to descending axons. In contrast both N-RGMa and NeICD overexpression resulted in aberrant axonal-paths, all of which suggests that it is a repulsive guidance molecule. Thus, two RGMa fragments activate distinct pathways resulting in different axonal responses. These data reveal how retinal projections are targeted to the appropriate layer in their target tissue.
authors: Genetics and Development and Vision Divisions, Toronto Western Research Institute, Krembil Discovery Tower, KDT-8-418, 60 Leonard Street, Toronto, ON, Canada M5T 2S8.|Department of Physiology, Faculty of Medicine, University of Toronto, 1 King's College circle, Toronto, ON, Canada M5S 1A8.
authors: P
authors: P
authors: Banerjee
authors: Genetics and Development and Vision Divisions, Toronto Western Research Institute, Krembil Discovery Tower, KDT-8-418, 60 Leonard Street, Toronto, ON, Canada M5T 2S8.|Department of Physiology, Faculty of Medicine, University of Toronto, 1 King's College circle, Toronto, ON, Canada M5S 1A8.
authors: H
authors: H
authors: Harada
authors: Genetics and Development and Vision Divisions, Toronto Western Research Institute, Krembil Discovery Tower, KDT-8-418, 60 Leonard Street, Toronto, ON, Canada M5T 2S8.|Department of Physiology, Faculty of Medicine, University of Toronto, 1 King's College circle, Toronto, ON, Canada M5S 1A8.
authors: N G
authors: NG
authors: Tassew
authors: Genetics and Development and Vision Divisions, Toronto Western Research Institute, Krembil Discovery Tower, KDT-8-418, 60 Leonard Street, Toronto, ON, Canada M5T 2S8.|Department of Physiology, Faculty of Medicine, University of Toronto, 1 King's College circle, Toronto, ON, Canada M5S 1A8.
authors: J
authors: J
authors: Charish
authors: Apoptosis, Cancer and Development Laboratory- Equipe labellisée 'La Ligue', Centre de Cancérologie de Lyon, INSERM U1052-CNRS UMR5286, Université de Lyon, Centre Léon Bérard, Lyon 69008, France.
authors: D
authors: D
authors: Goldschneider
authors: Genetics and Development and Vision Divisions, Toronto Western Research Institute, Krembil Discovery Tower, KDT-8-418, 60 Leonard Street, Toronto, ON, Canada M5T 2S8.|Department of Ophthalmology and Vision Science, Faculty of Medicine, University of Toronto, 340 College Street, Toronto, ON, Canada M5T 3A9.
authors: V A
authors: VA
authors: Wallace
authors: Genetics and Development and Vision Divisions, Toronto Western Research Institute, Krembil Discovery Tower, KDT-8-418, 60 Leonard Street, Toronto, ON, Canada M5T 2S8.|Department of Physiology, Faculty of Medicine, University of Toronto, 1 King's College circle, Toronto, ON, Canada M5S 1A8.
authors: S
authors: S
authors: Sugita
authors: Apoptosis, Cancer and Development Laboratory- Equipe labellisée 'La Ligue', Centre de Cancérologie de Lyon, INSERM U1052-CNRS UMR5286, Université de Lyon, Centre Léon Bérard, Lyon 69008, France.
authors: P
authors: P
authors: Mehlen
authors: Genetics and Development and Vision Divisions, Toronto Western Research Institute, Krembil Discovery Tower, KDT-8-418, 60 Leonard Street, Toronto, ON, Canada M5T 2S8.|Department of Physiology, Faculty of Medicine, University of Toronto, 1 King's College circle, Toronto, ON, Canada M5S 1A8.|Department of Ophthalmology and Vision Science, Faculty of Medicine, University of Toronto, 340 College Street, Toronto, ON, Canada M5T 3A9.
authors: P P
authors: PP
authors: Monnier
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000502:physiology*; D000818:Animals; D049108:Cell Enlargement; D002642:Chick Embryo; D009419:Nerve Tissue Proteins / Q000502:physiology*; D009928:Organ Specificity; D012165:Retinal Ganglion Cells / Q000502:physiology; D064067:Rho Guanine Nucleotide Exchange Factors / Q000502:physiology*; D013477:Superior Colliculi / Q000166:cytology / Q000201:enzymology; D046509:Tissue Culture Techniques
chemical_list: D009419:Nerve Tissue Proteins; D064067:Rho Guanine Nucleotide Exchange Factors; D053829:Amyloid Precursor Protein Secretases