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A role for the canonical nuclear factor-κB pathway in coupling neurotrophin-induced differential survival of developing spiral ganglion neurons.

Vandenbosch R, Chocholova E, Robe PA, Wang Y, Lambert C, Moonen G, Lallemend F, Malgrange B, Hadjab S - Front Cell Neurosci (2013)

Bottom Line: Using dissociated cultures of embryonic and postnatal spiral ganglion neurons, we observed a specific requirement of NFκB for BDNF but not NT3-dependent neuronal survival during a particular postnatal time window that corresponds to a period of neuronal cell death and hair cell innervation refinement in the developing cochlea.Consistently, postnatal p65 knockout mice showed a specific decreased number in type II spiral ganglion neurons.Taken together, these results identify NFκB as a type II neuron-specific factor that participates in the selective survival effects of BDNF and NT3 signaling on developing spiral ganglion neurons.

View Article: PubMed Central - PubMed

Affiliation: Groupe Interdisciplinaire de Génoprotéomique Appliquée-Neurosciences, Developmental Neurobiology Unit, University of Liège Liège, Belgium.

ABSTRACT
Neurotrophins are key players of neural development by controlling cell death programs. However, the signaling pathways that mediate their selective responses in different populations of neurons remain unclear. In the mammalian cochlea, sensory neurons differentiate perinatally into type I and II populations both expressing TrkB and TrkC, which bind respectively brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT3). How these two neuronal populations respond differentially to these two neurotrophins remains unknown. Here, we report in rat the segregation of the nuclear factor-κB (NFκB) subunit p65 specifically within the type II population postnatally. Using dissociated cultures of embryonic and postnatal spiral ganglion neurons, we observed a specific requirement of NFκB for BDNF but not NT3-dependent neuronal survival during a particular postnatal time window that corresponds to a period of neuronal cell death and hair cell innervation refinement in the developing cochlea. Consistently, postnatal p65 knockout mice showed a specific decreased number in type II spiral ganglion neurons. Taken together, these results identify NFκB as a type II neuron-specific factor that participates in the selective survival effects of BDNF and NT3 signaling on developing spiral ganglion neurons.

No MeSH data available.


Related in: MedlinePlus

NFκB is necessary for BDNF but not NT3-induced survival of postnatal SGNs.(A–C) SGNs were cultured for 24 h with BDNF or NT3 (each at 20 ng/ml) and in the presence of specific inhibitors of the NFκB signaling, SN50 (5 μM) (A,B) or sulfasalazine (1 mM, sz; P4, C). Note the absence of effect of the inhibitors on survival function of NT3 while they dramatically decrease the survival promoting action of BDNF (n = 3–8; *P < 0.05, **P < 0.01, ***P < 0.001; compared to neurotrophin alone).
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Figure 5: NFκB is necessary for BDNF but not NT3-induced survival of postnatal SGNs.(A–C) SGNs were cultured for 24 h with BDNF or NT3 (each at 20 ng/ml) and in the presence of specific inhibitors of the NFκB signaling, SN50 (5 μM) (A,B) or sulfasalazine (1 mM, sz; P4, C). Note the absence of effect of the inhibitors on survival function of NT3 while they dramatically decrease the survival promoting action of BDNF (n = 3–8; *P < 0.05, **P < 0.01, ***P < 0.001; compared to neurotrophin alone).

Mentions: The postnatal period is characterized by a refinement of the innervation of the organ of Corti by SGNs, and a concomitant loss of neurons within the type II population, which depends on BDNF for their survival (Barclay et al., 2011). To investigate the implication of NFκB in the signaling of the trophic support mediated by neurotrophins on SGNs during this critical period of development, SGNs from different stages of development, from embryonic (E18 and E19) or postnatal (P1, P2, P4, P6, and P8) animals, were cultured for 24 h in the presence of BDNF or NT3 together with specific inhibitors of the NFκB pathway, i.e., SN50 that blocks nuclear translocation of NFκB (Lin et al., 1995) and sulfasalazine (SZ) that interferes with the phosphorylation of IκBα (Wahl et al., 1998). Both neurotrophins were shown to significantly increase survival of SGNs (P < 0.01 at P8 and P < 0.001 at E18-P6, compared to control) from embryonic or postnatal animals, as previously shown (Malgrange et al., 1996; Mou et al., 1997, 1998). Strikingly, while inhibitors of NFκB did not affect the survival-promoting activity of NT3 at all stages analyzed (P > 0.05, Figures 5A,C), the trophic action of BDNF was specifically and only affected during the early postnatal period of development, from P1 to P6, with a maximum of inhibition observed at P4 (Figures 5B,C; P > 0.05, BDNF+SN50 compared to control). In addition to their survival action, neurotrophins have been shown to affect axonal growth both in vivo and in vitro (Defourny et al., 2011). Interestingly, inhibitors of NFκB did not change the BDNF-induced axon growth of SGNs from P4 animals (P > 0.05), suggesting a specific requirement of NFκB signaling for survival but not general axon growth promoted by BDNF.


A role for the canonical nuclear factor-κB pathway in coupling neurotrophin-induced differential survival of developing spiral ganglion neurons.

Vandenbosch R, Chocholova E, Robe PA, Wang Y, Lambert C, Moonen G, Lallemend F, Malgrange B, Hadjab S - Front Cell Neurosci (2013)

NFκB is necessary for BDNF but not NT3-induced survival of postnatal SGNs.(A–C) SGNs were cultured for 24 h with BDNF or NT3 (each at 20 ng/ml) and in the presence of specific inhibitors of the NFκB signaling, SN50 (5 μM) (A,B) or sulfasalazine (1 mM, sz; P4, C). Note the absence of effect of the inhibitors on survival function of NT3 while they dramatically decrease the survival promoting action of BDNF (n = 3–8; *P < 0.05, **P < 0.01, ***P < 0.001; compared to neurotrophin alone).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3842586&req=5

Figure 5: NFκB is necessary for BDNF but not NT3-induced survival of postnatal SGNs.(A–C) SGNs were cultured for 24 h with BDNF or NT3 (each at 20 ng/ml) and in the presence of specific inhibitors of the NFκB signaling, SN50 (5 μM) (A,B) or sulfasalazine (1 mM, sz; P4, C). Note the absence of effect of the inhibitors on survival function of NT3 while they dramatically decrease the survival promoting action of BDNF (n = 3–8; *P < 0.05, **P < 0.01, ***P < 0.001; compared to neurotrophin alone).
Mentions: The postnatal period is characterized by a refinement of the innervation of the organ of Corti by SGNs, and a concomitant loss of neurons within the type II population, which depends on BDNF for their survival (Barclay et al., 2011). To investigate the implication of NFκB in the signaling of the trophic support mediated by neurotrophins on SGNs during this critical period of development, SGNs from different stages of development, from embryonic (E18 and E19) or postnatal (P1, P2, P4, P6, and P8) animals, were cultured for 24 h in the presence of BDNF or NT3 together with specific inhibitors of the NFκB pathway, i.e., SN50 that blocks nuclear translocation of NFκB (Lin et al., 1995) and sulfasalazine (SZ) that interferes with the phosphorylation of IκBα (Wahl et al., 1998). Both neurotrophins were shown to significantly increase survival of SGNs (P < 0.01 at P8 and P < 0.001 at E18-P6, compared to control) from embryonic or postnatal animals, as previously shown (Malgrange et al., 1996; Mou et al., 1997, 1998). Strikingly, while inhibitors of NFκB did not affect the survival-promoting activity of NT3 at all stages analyzed (P > 0.05, Figures 5A,C), the trophic action of BDNF was specifically and only affected during the early postnatal period of development, from P1 to P6, with a maximum of inhibition observed at P4 (Figures 5B,C; P > 0.05, BDNF+SN50 compared to control). In addition to their survival action, neurotrophins have been shown to affect axonal growth both in vivo and in vitro (Defourny et al., 2011). Interestingly, inhibitors of NFκB did not change the BDNF-induced axon growth of SGNs from P4 animals (P > 0.05), suggesting a specific requirement of NFκB signaling for survival but not general axon growth promoted by BDNF.

Bottom Line: Using dissociated cultures of embryonic and postnatal spiral ganglion neurons, we observed a specific requirement of NFκB for BDNF but not NT3-dependent neuronal survival during a particular postnatal time window that corresponds to a period of neuronal cell death and hair cell innervation refinement in the developing cochlea.Consistently, postnatal p65 knockout mice showed a specific decreased number in type II spiral ganglion neurons.Taken together, these results identify NFκB as a type II neuron-specific factor that participates in the selective survival effects of BDNF and NT3 signaling on developing spiral ganglion neurons.

View Article: PubMed Central - PubMed

Affiliation: Groupe Interdisciplinaire de Génoprotéomique Appliquée-Neurosciences, Developmental Neurobiology Unit, University of Liège Liège, Belgium.

ABSTRACT
Neurotrophins are key players of neural development by controlling cell death programs. However, the signaling pathways that mediate their selective responses in different populations of neurons remain unclear. In the mammalian cochlea, sensory neurons differentiate perinatally into type I and II populations both expressing TrkB and TrkC, which bind respectively brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT3). How these two neuronal populations respond differentially to these two neurotrophins remains unknown. Here, we report in rat the segregation of the nuclear factor-κB (NFκB) subunit p65 specifically within the type II population postnatally. Using dissociated cultures of embryonic and postnatal spiral ganglion neurons, we observed a specific requirement of NFκB for BDNF but not NT3-dependent neuronal survival during a particular postnatal time window that corresponds to a period of neuronal cell death and hair cell innervation refinement in the developing cochlea. Consistently, postnatal p65 knockout mice showed a specific decreased number in type II spiral ganglion neurons. Taken together, these results identify NFκB as a type II neuron-specific factor that participates in the selective survival effects of BDNF and NT3 signaling on developing spiral ganglion neurons.

No MeSH data available.


Related in: MedlinePlus