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null mutant mice show long-term, incomplete retention of some afferent inner ear innervation\n\nAbstract\nBackground\nEars of Brn3c null mutants develop immature hair cells, identifiable only by certain molecular markers, and undergo apoptosis in neonates. This partial development of hair cells could lead to enough neurotrophin expression to sustain sensory neurons through embryonic development. We have therefore investigated in these mutants the patterns of innervation and of expression of known neurotrophins.\n\nResults\nAt birth there is a limited expression of BDNF and NT-3 in the mutant sensory epithelia and DiI tracing shows no specific reduction of afferents or efferents that resembles neurotrophin null mutations. At postnatal day 7/8 (P7/8), innervation is severely reduced both qualitatively and quantitatively. 1% of myosin VIIa-positive immature hair cells are present in the mutant cochlea, concentrated in the base. Around 20% of immature hair cells exist in the mutant vestibular sensory epithelia. Despite more severe loss of hair cells (1% compared to 20%), the cochlea retains many more sensory neurons (46% compared to 15%) than vestibular epithelia. Even 6 months old mutant mice have some fibers to all vestibular sensory epithelia and many more to the cochlear apex which lacks MyoVIIa positive hair cells. Topologically organized central cochlea projections exist at least until P8, suggesting that functional hair cells are not required to establish such projections.\n\nConclusion\nThe limited expression of neurotrophins in the cochlea of Brn3c null mice suffices to support many sensory neurons, particularly in the cochlea, until birth. The molecular nature of the long term survival of apical spiral neurons remains unclear.\n\nBackground\nBrn3c is a POU domain factor that is crucial for inner ear hair cell development. Targeted null Brn3c mutants have no mature hair cells [1,2]. Close examination has revealed that some 'immature' hair cells form in Brn3c null mutants and express cellular markers such as Myosin VI and VIIa, calretinin and parvalbumin [3]. Furthermore, these immature hair cells of Brn3c null mutants undergo apoptosis in neonates [3]. Consistent with an apparent absence of mature hair cells, initial work suggested that all vestibular and most spiral ganglion cells are lost by postnatal day 14 (P14; [1]). However, more detailed quantification by others [3] reported that at P4 about 77% of vestibular neurons and only 29% of spiral neurons are lost. It was suggested that there is possibly a complete loss in adults [3]. Other than these preliminary statements, no data exists concerning the detailed pattern of loss of innervation in Brn3c null mutants.\nThe initial development and partial differentiation of hair cells in Brn3c mutants could possibly lead to some neurotrophin expression in these cells to sustain sensory neurons through embryonic development and beyond. Data on various single and compound neurotrophin null mutants have shown that the loss of a specific neurotrophin leads to topologically restricted loss of sensory neurons in the embryonic ear [4,5]. Such selective loss in Brn3c null mutants would therefore indicate reduction of a specific neurotrophin in immature hair cells. Moreover, recent work shows that in embryos NT-3 is primarily expressed in supporting cells, moving only around birth into hair cells [6,7]. In fact, the selective loss of vestibular as compared to cochlear sensory neurons (77% versus 29%; [3]) suggests that NT-3 expression may be less downregulated in Brn3c null mutants than BDNF [6,8,9], provided that at least some differentiation of supporting cells takes place. In the ear [4] as well as elsewhere [10] neurotrophins are progressively downregulated in postnatal mammals and possibly replaced by other factors [11].\nWe have investigated in detail the pattern of innervation in the Brn3c mutants, as well as the expression of NT-3 and BDNF. We want to evaluate a possible correlation between the topology of sensory neuron loss and absence of a specific neurotrophin or topological loss of hair cells at birth and in older animals. This information could be important for an in-depth evaluation of the human deafness related to the Pou4f3 gene, DFNA15 [12].\nWe report here long term retention of cochlear sensory neurons for at least 6 months, in particular in the cochlear apex, in Brn3c null mutant mice. This retention of afferents and efferents is unrelated to hair cell differentiation as not even immature hair cells can be detected at early postnatal stages with MyoVII immunocytochemistry in this part of the cochlea. This retention of apical spiral neurons is also largely unrelated to neurotrophins which are known to be reduced in their expression in neonatal rodents [4].\n\nResults\nTo appreciate the effects of the Brn3c null mutation on the pattern of the inner ear innervation, we first want to present the effects of BDNF and NT-3 null mutations at birth [6,13,14]. Null mutants of BDNF or its receptor trkB lose all innervation to the semicircular canals and have a reduced innervation to the utricle, saccule and apical turn of the cochlea. In contrast, null mutations of either NT-3 or its receptor trkC result in loss of spiral neurons in the basal turn with formation of an inner spiral bundle of afferents extending to the basal tip. Our null hypothesis for this study would be that Brn3c null mice show severe compromised production of these neurotrophins and should therefore show a comparable pattern of nerve fiber loss.\n\nBrn3c n"}

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null mutant mice show long-term, incomplete retention of some afferent inner ear innervation\n\nAbstract\nBackground\nEars of Brn3c null mutants develop immature hair cells, identifiable only by certain molecular markers, and undergo apoptosis in neonates. This partial development of hair cells could lead to enough neurotrophin expression to sustain sensory neurons through embryonic development. We have therefore investigated in these mutants the patterns of innervation and of expression of known neurotrophins.\n\nResults\nAt birth there is a limited expression of BDNF and NT-3 in the mutant sensory epithelia and DiI tracing shows no specific reduction of afferents or efferents that resembles neurotrophin null mutations. At postnatal day 7/8 (P7/8), innervation is severely reduced both qualitatively and quantitatively. 1% of myosin VIIa-positive immature hair cells are present in the mutant cochlea, concentrated in the base. Around 20% of immature hair cells exist in the mutant vestibular sensory epithelia. Despite more severe loss of hair cells (1% compared to 20%), the cochlea retains many more sensory neurons (46% compared to 15%) than vestibular epithelia. Even 6 months old mutant mice have some fibers to all vestibular sensory epithelia and many more to the cochlear apex which lacks MyoVIIa positive hair cells. Topologically organized central cochlea projections exist at least until P8, suggesting that functional hair cells are not required to establish such projections.\n\nConclusion\nThe limited expression of neurotrophins in the cochlea of Brn3c null mice suffices to support many sensory neurons, particularly in the cochlea, until birth. The molecular nature of the long term survival of apical spiral neurons remains unclear.\n\nBackground\nBrn3c is a POU domain factor that is crucial for inner ear hair cell development. Targeted null Brn3c mutants have no mature hair cells [1,2]. Close examination has revealed that some 'immature' hair cells form in Brn3c null mutants and express cellular markers such as Myosin VI and VIIa, calretinin and parvalbumin [3]. Furthermore, these immature hair cells of Brn3c null mutants undergo apoptosis in neonates [3]. Consistent with an apparent absence of mature hair cells, initial work suggested that all vestibular and most spiral ganglion cells are lost by postnatal day 14 (P14; [1]). However, more detailed quantification by others [3] reported that at P4 about 77% of vestibular neurons and only 29% of spiral neurons are lost. It was suggested that there is possibly a complete loss in adults [3]. Other than these preliminary statements, no data exists concerning the detailed pattern of loss of innervation in Brn3c null mutants.\nThe initial development and partial differentiation of hair cells in Brn3c mutants could possibly lead to some neurotrophin expression in these cells to sustain sensory neurons through embryonic development and beyond. Data on various single and compound neurotrophin null mutants have shown that the loss of a specific neurotrophin leads to topologically restricted loss of sensory neurons in the embryonic ear [4,5]. Such selective loss in Brn3c null mutants would therefore indicate reduction of a specific neurotrophin in immature hair cells. Moreover, recent work shows that in embryos NT-3 is primarily expressed in supporting cells, moving only around birth into hair cells [6,7]. In fact, the selective loss of vestibular as compared to cochlear sensory neurons (77% versus 29%; [3]) suggests that NT-3 expression may be less downregulated in Brn3c null mutants than BDNF [6,8,9], provided that at least some differentiation of supporting cells takes place. In the ear [4] as well as elsewhere [10] neurotrophins are progressively downregulated in postnatal mammals and possibly replaced by other factors [11].\nWe have investigated in detail the pattern of innervation in the Brn3c mutants, as well as the expression of NT-3 and BDNF. We want to evaluate a possible correlation between the topology of sensory neuron loss and absence of a specific neurotrophin or topological loss of hair cells at birth and in older animals. This information could be important for an in-depth evaluation of the human deafness related to the Pou4f3 gene, DFNA15 [12].\nWe report here long term retention of cochlear sensory neurons for at least 6 months, in particular in the cochlear apex, in Brn3c null mutant mice. This retention of afferents and efferents is unrelated to hair cell differentiation as not even immature hair cells can be detected at early postnatal stages with MyoVII immunocytochemistry in this part of the cochlea. This retention of apical spiral neurons is also largely unrelated to neurotrophins which are known to be reduced in their expression in neonatal rodents [4].\n\nResults\nTo appreciate the effects of the Brn3c null mutation on the pattern of the inner ear innervation, we first want to present the effects of BDNF and NT-3 null mutations at birth [6,13,14]. Null mutants of BDNF or its receptor trkB lose all innervation to the semicircular canals and have a reduced innervation to the utricle, saccule and apical turn of the cochlea. In contrast, null mutations of either NT-3 or its receptor trkC result in loss of spiral neurons in the basal turn with formation of an inner spiral bundle of afferents extending to the basal tip. Our null hypothesis for this study would be that Brn3c null mice show severe compromised production of these neurotrophins and should therefore show a comparable pattern of nerve fiber loss.\n\nBrn3c n"}

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null mutant mice show long-term, incomplete retention of some afferent inner ear innervation\n\nAbstract\nBackground\nEars of Brn3c null mutants develop immature hair cells, identifiable only by certain molecular markers, and undergo apoptosis in neonates. This partial development of hair cells could lead to enough neurotrophin expression to sustain sensory neurons through embryonic development. We have therefore investigated in these mutants the patterns of innervation and of expression of known neurotrophins.\n\nResults\nAt birth there is a limited expression of BDNF and NT-3 in the mutant sensory epithelia and DiI tracing shows no specific reduction of afferents or efferents that resembles neurotrophin null mutations. At postnatal day 7/8 (P7/8), innervation is severely reduced both qualitatively and quantitatively. 1% of myosin VIIa-positive immature hair cells are present in the mutant cochlea, concentrated in the base. Around 20% of immature hair cells exist in the mutant vestibular sensory epithelia. Despite more severe loss of hair cells (1% compared to 20%), the cochlea retains many more sensory neurons (46% compared to 15%) than vestibular epithelia. Even 6 months old mutant mice have some fibers to all vestibular sensory epithelia and many more to the cochlear apex which lacks MyoVIIa positive hair cells. Topologically organized central cochlea projections exist at least until P8, suggesting that functional hair cells are not required to establish such projections.\n\nConclusion\nThe limited expression of neurotrophins in the cochlea of Brn3c null mice suffices to support many sensory neurons, particularly in the cochlea, until birth. The molecular nature of the long term survival of apical spiral neurons remains unclear.\n\nBackground\nBrn3c is a POU domain factor that is crucial for inner ear hair cell development. Targeted null Brn3c mutants have no mature hair cells [1,2]. Close examination has revealed that some 'immature' hair cells form in Brn3c null mutants and express cellular markers such as Myosin VI and VIIa, calretinin and parvalbumin [3]. Furthermore, these immature hair cells of Brn3c null mutants undergo apoptosis in neonates [3]. Consistent with an apparent absence of mature hair cells, initial work suggested that all vestibular and most spiral ganglion cells are lost by postnatal day 14 (P14; [1]). However, more detailed quantification by others [3] reported that at P4 about 77% of vestibular neurons and only 29% of spiral neurons are lost. It was suggested that there is possibly a complete loss in adults [3]. Other than these preliminary statements, no data exists concerning the detailed pattern of loss of innervation in Brn3c null mutants.\nThe initial development and partial differentiation of hair cells in Brn3c mutants could possibly lead to some neurotrophin expression in these cells to sustain sensory neurons through embryonic development and beyond. Data on various single and compound neurotrophin null mutants have shown that the loss of a specific neurotrophin leads to topologically restricted loss of sensory neurons in the embryonic ear [4,5]. Such selective loss in Brn3c null mutants would therefore indicate reduction of a specific neurotrophin in immature hair cells. Moreover, recent work shows that in embryos NT-3 is primarily expressed in supporting cells, moving only around birth into hair cells [6,7]. In fact, the selective loss of vestibular as compared to cochlear sensory neurons (77% versus 29%; [3]) suggests that NT-3 expression may be less downregulated in Brn3c null mutants than BDNF [6,8,9], provided that at least some differentiation of supporting cells takes place. In the ear [4] as well as elsewhere [10] neurotrophins are progressively downregulated in postnatal mammals and possibly replaced by other factors [11].\nWe have investigated in detail the pattern of innervation in the Brn3c mutants, as well as the expression of NT-3 and BDNF. We want to evaluate a possible correlation between the topology of sensory neuron loss and absence of a specific neurotrophin or topological loss of hair cells at birth and in older animals. This information could be important for an in-depth evaluation of the human deafness related to the Pou4f3 gene, DFNA15 [12].\nWe report here long term retention of cochlear sensory neurons for at least 6 months, in particular in the cochlear apex, in Brn3c null mutant mice. This retention of afferents and efferents is unrelated to hair cell differentiation as not even immature hair cells can be detected at early postnatal stages with MyoVII immunocytochemistry in this part of the cochlea. This retention of apical spiral neurons is also largely unrelated to neurotrophins which are known to be reduced in their expression in neonatal rodents [4].\n\nResults\nTo appreciate the effects of the Brn3c null mutation on the pattern of the inner ear innervation, we first want to present the effects of BDNF and NT-3 null mutations at birth [6,13,14]. Null mutants of BDNF or its receptor trkB lose all innervation to the semicircular canals and have a reduced innervation to the utricle, saccule and apical turn of the cochlea. In contrast, null mutations of either NT-3 or its receptor trkC result in loss of spiral neurons in the basal turn with formation of an inner spiral bundle of afferents extending to the basal tip. Our null hypothesis for this study would be that Brn3c null mice show severe compromised production of these neurotrophins and should therefore show a comparable pattern of nerve fiber loss.\n\nBrn3c n"}