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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

Loss of type II SGNs in p65-deficient mice.(A,B) Immunostaining for peripherin on SG sections from Tnfr1-/-(A) and Tnfr1-/-; p65-/- mice (B), showing dramatic loss of type II population in the absence of p65. (C) Quantification of (A,B) (n = 3; **P < 0.01). (D–G) Immunostaining for βIII-tubulin, BDNF and peripherin on sections of organ of Corti (D,F) or SG (E,G) from P0 (D,E) and P3 (F,G) mouse cochlea. Note expression of BDNF in the OHC (1 to 3) and IHC (asterisk) at P0 (D) but not at P3 (F). Also, while BDNF expression is observed in afferent endings of IHC and OHC at both P0 (D) and P3 (F), it is hardly seen in the soma of SGNs at P0 (E, arrow points to a positive afferent), but upregulated there at P3.
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Figure 6: Loss of type II SGNs in p65-deficient mice.(A,B) Immunostaining for peripherin on SG sections from Tnfr1-/-(A) and Tnfr1-/-; p65-/- mice (B), showing dramatic loss of type II population in the absence of p65. (C) Quantification of (A,B) (n = 3; **P < 0.01). (D–G) Immunostaining for βIII-tubulin, BDNF and peripherin on sections of organ of Corti (D,F) or SG (E,G) from P0 (D,E) and P3 (F,G) mouse cochlea. Note expression of BDNF in the OHC (1 to 3) and IHC (asterisk) at P0 (D) but not at P3 (F). Also, while BDNF expression is observed in afferent endings of IHC and OHC at both P0 (D) and P3 (F), it is hardly seen in the soma of SGNs at P0 (E, arrow points to a positive afferent), but upregulated there at P3.

Mentions: To examine the requirement for p65 during development of type II neurons in vivo, we changed the model system and analyzed mutant mice for p65. Since p65-/- mice die at E14–15 from massive liver apoptosis mediated through TNFR1 signaling (Beg et al., 1995; Rosenfeld et al., 2000), we generated mice that were deficient in both p65 and Tnfr1 and analyzed neuronal phenotype in cochlea of young adult animals (P21). Interestingly, although the total number of SGNs (i.e., βIII-tubulin+ cells per section) showed no significant difference between Tnfr1-/- and Tnfr1-/-; p65-/- mice (Tnfr1-/-; p65+/+: 92.3 ± 14.4; Tnfr1-/-; p65-/-: 74 ± 4.8, n = 3, P > 0.1), the number of peripherin+ type II neurons (which only represents around 10% of the whole neuronal population) was dramatically reduced in the absence of p65 (Figures 6A–C), whereas experiments with wild-type mice yielded similar numbers as seen for Tnfr1-/-; p65+/+ (data not shown). Together with our in vitro analysis, these data show that BDNF through NFκB signaling is required to support a significant fraction of the type II neuronal population during early postnatal development of the cochlea.


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)

Loss of type II SGNs in p65-deficient mice.(A,B) Immunostaining for peripherin on SG sections from Tnfr1-/-(A) and Tnfr1-/-; p65-/- mice (B), showing dramatic loss of type II population in the absence of p65. (C) Quantification of (A,B) (n = 3; **P < 0.01). (D–G) Immunostaining for βIII-tubulin, BDNF and peripherin on sections of organ of Corti (D,F) or SG (E,G) from P0 (D,E) and P3 (F,G) mouse cochlea. Note expression of BDNF in the OHC (1 to 3) and IHC (asterisk) at P0 (D) but not at P3 (F). Also, while BDNF expression is observed in afferent endings of IHC and OHC at both P0 (D) and P3 (F), it is hardly seen in the soma of SGNs at P0 (E, arrow points to a positive afferent), but upregulated there at P3.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Figure 6: Loss of type II SGNs in p65-deficient mice.(A,B) Immunostaining for peripherin on SG sections from Tnfr1-/-(A) and Tnfr1-/-; p65-/- mice (B), showing dramatic loss of type II population in the absence of p65. (C) Quantification of (A,B) (n = 3; **P < 0.01). (D–G) Immunostaining for βIII-tubulin, BDNF and peripherin on sections of organ of Corti (D,F) or SG (E,G) from P0 (D,E) and P3 (F,G) mouse cochlea. Note expression of BDNF in the OHC (1 to 3) and IHC (asterisk) at P0 (D) but not at P3 (F). Also, while BDNF expression is observed in afferent endings of IHC and OHC at both P0 (D) and P3 (F), it is hardly seen in the soma of SGNs at P0 (E, arrow points to a positive afferent), but upregulated there at P3.
Mentions: To examine the requirement for p65 during development of type II neurons in vivo, we changed the model system and analyzed mutant mice for p65. Since p65-/- mice die at E14–15 from massive liver apoptosis mediated through TNFR1 signaling (Beg et al., 1995; Rosenfeld et al., 2000), we generated mice that were deficient in both p65 and Tnfr1 and analyzed neuronal phenotype in cochlea of young adult animals (P21). Interestingly, although the total number of SGNs (i.e., βIII-tubulin+ cells per section) showed no significant difference between Tnfr1-/- and Tnfr1-/-; p65-/- mice (Tnfr1-/-; p65+/+: 92.3 ± 14.4; Tnfr1-/-; p65-/-: 74 ± 4.8, n = 3, P > 0.1), the number of peripherin+ type II neurons (which only represents around 10% of the whole neuronal population) was dramatically reduced in the absence of p65 (Figures 6A–C), whereas experiments with wild-type mice yielded similar numbers as seen for Tnfr1-/-; p65+/+ (data not shown). Together with our in vitro analysis, these data show that BDNF through NFκB signaling is required to support a significant fraction of the type II neuronal population during early postnatal development of the cochlea.

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