ALBERT

Description: Publication date: Available online 6 August 2015 Source: Cell Reports Author(s): Jenea M. Bin, Dong Han, Karen Lai Wing Sun, Louis-Philippe Croteau, Emilie Dumontier, Jean-Francois Cloutier, Artur Kania, Timothy E. Kennedy 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. Graphical abstract Teaser Bin et al. have generated a netrin-1 null mouse that displays phenotypes more severe than those of the reported netrin-1 gene-trap mouse, including embryonic lethality and exacerbated axon guidance defects. No increased apoptosis was detected, indicating that netrin-1 is not an essential dependence ligand, despite increased DCC and neogenin in netrin-1 nulls.