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Cell Rep. 2015 Aug 18;12(7):1099-106. doi: 10.1016/j.celrep.2015.07.028. Epub 2015 Aug 6.

Complete Loss of Netrin-1 Results in Embryonic Lethality and Severe Axon Guidance Defects without Increased Neural Cell Death.

Author information

1
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.
2
Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montréal, QC H3A 2B4, Canada.
3
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.
4
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.

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.

PMID:
26257176
DOI:
10.1016/j.celrep.2015.07.028
[Indexed for MEDLINE]
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