The inactivation of the sortilin gene leads to a partial disruption of prosaposin trafficking to the lysosomes

Zeng, Jibin; Racicott, Jesse; Morales, Carlos R.

doi:10.1016/j.yexcr.2009.08.016

Cited by 50 publications

(42 citation statements)

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“…The homologous recombination resulted in the replacement of a segment between exons 2 and intron 3 of the sortilin gene with the neomycin resistance cassette. Chimeric cells were injected into C57BL/6 blastocysts giving rise to chimeric mice, which were then backcrossed to C57BL/6 mice to identify if the germ-line transmission of the mutant allele had taken place (52). These heterozygotes were backcrossed with C57BL/6 mice for a minimum of seven generations before they were used in this study.…”

Section: Methodsmentioning

confidence: 99%

ProNGF induces TNFα-dependent death of retinal ganglion cells through a p75 ^NTR non-cell-autonomous signaling pathway

Lebrun-Julien

Bertrand

Backer

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Neurotrophin binding to the p75 neurotrophin receptor (p75 NTR ) activates neuronal apoptosis following adult central nervous system injury, but the underlying cellular mechanisms remain poorly defined. In this study, we show that the proform of nerve growth factor (proNGF) induces death of retinal ganglion cells in adult rodents via a p75 NTR -dependent signaling mechanism. Expression of p75 NTR in the adult retina is confined to Müller glial cells; therefore we tested the hypothesis that proNGF activates a non-cellautonomous signaling pathway to induce retinal ganglion cell (RGC) death. Consistent with this, we show that proNGF induced robust expression of tumor necrosis factor alpha (TNFα) in Müller cells and that genetic or biochemical ablation of TNFα blocked proNGF-induced death of retinal neurons. Mice rendered null for p75 NTR , its coreceptor sortilin, or the adaptor protein NRAGE were defective in proNGF-induced glial TNFα production and did not undergo proNGF-induced retinal ganglion cell death. We conclude that proNGF activates a non-cell-autonomous signaling pathway that causes TNFα-dependent death of retinal neurons in vivo.T he four mammalian neurotrophins comprise a family of related secreted factors that are required for differentiation, survival, development, and death of specific populations of neurons and nonneuronal cells. Neurotrophins are produced as proforms of ∼240 amino acids that are cleaved by furins and proconvertases to yield products of ∼120 amino acids. Recent studies have indicated that nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) can be secreted as proforms in the central nervous system (CNS) (1-3) and demonstrated that proneurotrophins can function as potent apoptosis-inducing ligands both in vitro and in vivo (4). However, the precise mechanisms by which proneurotrophins lead to neuronal death are poorly defined.The biological effects of neurotrophins are mediated by binding to TrkA, TrkB, and TrkC receptor tyrosine kinases and to the p75 neurotrophin receptor (p75 NTR ). Trk receptors respond preferentially to mature neurotrophins whereas proneurotrophins exert their apoptotic effect via a receptor complex that contains p75 NTR and sortilin (5). The precise signaling cascades evoked by occupancy of the p75 NTR -sortilin complex remain to be elucidated, but several lines of evidence indicate that NRIF and NRAGE adaptor proteins play key roles in death signaling cascades evoked by p75 NTR (6, 7).Previous studies have shown that neurotrophins induce cell death via p75 NTR during early retinal development (8). p75 NTR has also been implicated in light-induced photoreceptor death in adult rodents in vivo (9) and a proNGF-p75 NTR link has been proposed to facilitate apoptosis in a retinal cell line (10). Here, we investigate the role of proNGF in the adult retina and demonstrate that proNGF promotes death of retinal ganglion cells (RGCs) in vivo. Importantly, proNGF-induced RGC loss is indirect and requires the p75 NTRdependent production of tumor necrosis...

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Section: Methodsmentioning

confidence: 99%

ProNGF induces TNFα-dependent death of retinal ganglion cells through a p75 ^NTR non-cell-autonomous signaling pathway

Lebrun-Julien

Bertrand

Backer

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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111

100

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“…Sort1 knockout can rescue midline defects in a Shhprocessing mutant Germline Sort1-knockout (Sort1 −/− ) is not associated with developmental defects, including phenotypes associated with altered Hh signaling (Jansen et al, 2007;Zeng et al, 2009). Therefore, to examine whether Sort1 function impacts Shh processing in vivo, we examined its effect in a sensitized system using a processing-deficient Shh-mutant mouse model, Shh::GFP (Chamberlain et al, 2008).…”

Section: Sort1 Promotes the Accumulation Of Shh In The Golgi And Redumentioning

confidence: 99%

Sortilin regulates sorting and secretion of Sonic hedgehog

Campbell

Beug

Nickerson

et al. 2016

Journal of Cell Science

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Sonic Hedgehog (Shh) is a secreted morphogen that is an essential regulatorof patterning and growth. The Shh full-length protein undergoes autocleavage in the endoplasmic reticulum to generate the biologically active N-terminal fragment (ShhN), which is destined for secretion. We identified sortilin (Sort1), a member of the VPS10P-domain receptor family, as a new Shh trafficking receptor. We demonstrate that Sort-Shh interact by performing coimmunoprecipitation and proximity ligation assays in transfected cells and that they colocalize at the Golgi. Sort1 overexpression causes re-distribution of ShhN and, to a lesser extent, of full-length Shh to the Golgi and reduces Shh secretion. We show loss of Sort1 can partially rescue Hedgehog-associated patterning defects in a mouse model that is deficient in Shh processing, and we show that Sort1 levels negatively regulate anterograde Shh transport in axons in vitro and Hedgehog-dependent axon-glial interactions in vivo. Taken together, we conclude that Shh and Sort1 can interact at the level of the Golgi and that Sort1 directs Shh away from the pathways that promote its secretion.

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“…Therefore, because elevated levels of Sort1 retain Shh proteins in the Golgi and reduce Shh secretion, we suggest that Sort1 functions as a sorting receptor that binds to ShhN in the Golgi and directs ShhN away from pathways that destine Shh for secretion. altered Hh signaling (Jansen et al, 2007;Zeng et al, 2009). Therefore, to examine whether Sort1 function impacts Shh processing in vivo, we examined its effect in a sensitized system using a processing-deficient Shh-mutant mouse model, Shh::GFP (Chamberlain et al, 2008).…”

Section: Sort1 Promotes the Accumulation Of Shh In The Golgi And Redumentioning

confidence: 99%

“…Wild-type CD1 mice (Charles River) were used for the isolation of primary cortical neurons. Sort1-mutant (Sort1 −/− ) mice (genotyped by performing PCR using the following primers: F -5′-CTC-AGGAATGGCATTCTCAG-3′, R -5′-AGCCTTTACCTGGTGTCATC-3′) (Zeng et al, 2009) and Shh::GFP mice (Jackson Labs) [genotyped as described previously (Chamberlain et al, 2008)] were maintained on a C57/ Bl6J background (Charles River). F2 mice from Sort1 +/− ×Shh +/GFP matings were mated to generate Sort1;Shh::GFP double mutants and littermate controls at E11.5 and E14.5.…”

Section: Mouse Lines and In Utero Electroporationmentioning

confidence: 99%

“…Sort1, the prototypic family member, is involved in targeting ligands, including neurotrophins and neurotrophin receptors, to various intracellular compartments, including the endosomal and regulated secretory pathway (RSP) Evans et al, 2011;Vaegter et al, 2011;Yang et al, 2011), and lysosomes (Canuel et al, 2008;Evans et al, 2011;Hassan et al, 2004;Lefrancois et al, 2003;Ni and Morales, 2006;Yang et al, 2013;Zeng et al, 2009). Sort1 also functions as a cell surface receptor for neurotrophins and other growth factors (Nykjaer et al, 2004;Teng et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

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Sortilin regulates sorting and secretion of Sonic hedgehog

et al. 2016

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The inactivation of the sortilin gene leads to a partial disruption of prosaposin trafficking to the lysosomes

Cited by 50 publications

References 46 publications

ProNGF induces TNFα-dependent death of retinal ganglion cells through a p75 ^NTR non-cell-autonomous signaling pathway

ProNGF induces TNFα-dependent death of retinal ganglion cells through a p75 ^NTR non-cell-autonomous signaling pathway

Sortilin regulates sorting and secretion of Sonic hedgehog

Sortilin regulates sorting and secretion of Sonic hedgehog

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The inactivation of the sortilin gene leads to a partial disruption of prosaposin trafficking to the lysosomes

Cited by 50 publications

References 46 publications

ProNGF induces TNFα-dependent death of retinal ganglion cells through a p75 NTR non-cell-autonomous signaling pathway

ProNGF induces TNFα-dependent death of retinal ganglion cells through a p75 NTR non-cell-autonomous signaling pathway

Sortilin regulates sorting and secretion of Sonic hedgehog

Sortilin regulates sorting and secretion of Sonic hedgehog

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ProNGF induces TNFα-dependent death of retinal ganglion cells through a p75 ^NTR non-cell-autonomous signaling pathway

ProNGF induces TNFα-dependent death of retinal ganglion cells through a p75 ^NTR non-cell-autonomous signaling pathway