title: Complete Loss of Netrin-1 Results in Embryonic Lethality and Severe Axon Guidance Defects without Increased Neural Cell Death.
abstract: Netrin-1 regulates cell migration and adhesion during the development of the nervous system, vasculature, lung, pancreas, muscle, and mammary gland. It is also proposed to function as a dependence ligand that inhibits apoptosis; however, studies disagree regarding whether netrin-1 loss-of-function mice exhibit increased cell death. Furthermore, previously studied netrin-1 loss-of-function gene-trap mice express a netrin-1-β-galactosidase protein chimera with potential for toxic gain-of-function effects, as well as a small amount of wild-type netrin-1 protein. To unambiguously assess loss of function, we generated netrin-1 floxed and netrin-1 null mouse lines. Netrin-1(-/-) mice die earlier and exhibit more severe axon guidance defects than netrin-1 gene-trap mice, revealing that complete loss of function is more severe than previously reported. Netrin-1(-/-) embryos also exhibit increased expression of the netrin receptors DCC and neogenin that are proposed dependence receptors; however, increased apoptosis was not detected, inconsistent with netrin-1 being an essential dependence receptor ligand in the embryonic spinal cord.
authors.affiliation: Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montréal, QC H3A 2B4, Canada; Integrated Program in Neuroscience, McGill University, Montréal, QC H3A 2B2, Canada.
authors.forename: Jenea M
authors.initials: JM
authors.lastname: Bin
authors.affiliation: Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montréal, QC H3A 2B4, Canada.
authors.forename: Dong
authors.initials: D
authors.lastname: Han
authors.affiliation: Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montréal, QC H3A 2B4, Canada; Integrated Program in Neuroscience, McGill University, Montréal, QC H3A 2B2, Canada.
authors.forename: Karen
authors.initials: K
authors.lastname: Lai Wing Sun
authors.affiliation: Institut de Recherches Cliniques de Montréal (IRCM), Montréal, QC H2W 1R7, Canada; Integrated Program in Neuroscience, McGill University, Montréal, QC H3A 2B2, Canada; Division of Experimental Medicine, Departments of Anatomy and Cell Biology, and Biology, McGill University Montréal, QC H3A 2B2, Canada; Faculté de Médecine, Université de Montréal, Montréal, QC H3C 3J7, Canada.
authors.forename: Louis-Philippe
authors.initials: LP
authors.lastname: Croteau
authors.affiliation: Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montréal, QC H3A 2B4, Canada.
authors.forename: Emilie
authors.initials: E
authors.lastname: Dumontier
authors.affiliation: Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montréal, QC H3A 2B4, Canada; Integrated Program in Neuroscience, McGill University, Montréal, QC H3A 2B2, Canada.
authors.forename: Jean-Francois
authors.initials: JF
authors.lastname: Cloutier
authors.affiliation: Institut de Recherches Cliniques de Montréal (IRCM), Montréal, QC H2W 1R7, Canada; Integrated Program in Neuroscience, McGill University, Montréal, QC H3A 2B2, Canada; Division of Experimental Medicine, Departments of Anatomy and Cell Biology, and Biology, McGill University Montréal, QC H3A 2B2, Canada; Faculté de Médecine, Université de Montréal, Montréal, QC H3C 3J7, Canada.
authors.forename: Artur
authors.initials: A
authors.lastname: Kania
authors.affiliation: Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montréal, QC H3A 2B4, Canada; Integrated Program in Neuroscience, McGill University, Montréal, QC H3A 2B2, Canada. Electronic address: timothy.kennedy@mcgill.ca.
authors.forename: Timothy E
authors.initials: TE
authors.lastname: Kennedy
mesh_terms: D000818:Animals; D017209:Apoptosis; D001369:Axons / Q000378:metabolism* / Q000473:pathology; D004622:Embryo, Mammalian / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005313:Fetal Death; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009414:Nerve Growth Factors / Q000235:genetics* / Q000378:metabolism; D000075386:Netrin Receptors; D000075388:Netrin-1; D011247:Pregnancy; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D008565:Membrane Proteins; D009414:Nerve Growth Factors; D000075386:Netrin Receptors; C000617353:Ntn1 protein, mouse; D011956:Receptors, Cell Surface; D025521:Tumor Suppressor Proteins; C091279:neogenin; D000075388:Netrin-1