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Neurod1 suppresses hair cell differentiation in ear ganglia and regulates hair cell subtype development in the cochlea.

Jahan I, Pan N, Kersigo J, Fritzsch B - PLoS ONE (2010)

Bottom Line: Our data suggest that the long noted cross-regulation of Atoh1 expression by Neurog1 might actually be mediated in large part by Neurod1.We suggest that Neurod1 is regulated by both Neurog1 and Atoh1 and provides a negative feedback for either gene.Through this and other feedback, Neurod1 suppresses alternate fates of neurons to differentiate as hair cells and regulates hair cell subtypes.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, University of Iowa, Iowa City, Iowa, United States of America.

ABSTRACT

Background: At least five bHLH genes regulate cell fate determination and differentiation of sensory neurons, hair cells and supporting cells in the mammalian inner ear. Cross-regulation of Atoh1 and Neurog1 results in hair cell changes in Neurog1 mice although the nature and mechanism of the cross-regulation has not yet been determined. Neurod1, regulated by both Neurog1 and Atoh1, could be the mediator of this cross-regulation.

Methodology/principal findings: We used Tg(Pax2-Cre) to conditionally delete Neurod1 in the inner ear. Our data demonstrate for the first time that the absence of Neurod1 results in formation of hair cells within the inner ear sensory ganglia. Three cell types, neural crest derived Schwann cells and mesenchyme derived fibroblasts (neither expresses Neurod1) and inner ear derived neurons (which express Neurod1) constitute inner ear ganglia. The most parsimonious explanation is that Neurod1 suppresses the alternative fate of sensory neurons to develop as hair cells. In the absence of Neurod1, Atoh1 is expressed and differentiates cells within the ganglion into hair cells. We followed up on this effect in ganglia by demonstrating that Neurod1 also regulates differentiation of subtypes of hair cells in the organ of Corti. We show that in Neurod1 conditional mice there is a premature expression of several genes in the apex of the developing cochlea and outer hair cells are transformed into inner hair cells.

Conclusions/significance: Our data suggest that the long noted cross-regulation of Atoh1 expression by Neurog1 might actually be mediated in large part by Neurod1. We suggest that Neurod1 is regulated by both Neurog1 and Atoh1 and provides a negative feedback for either gene. Through this and other feedback, Neurod1 suppresses alternate fates of neurons to differentiate as hair cells and regulates hair cell subtypes.

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Neurod1 regulates neuronal differentiation by suppression of premature hair cell differentiation of neurons possibly interacting with several target genes.In the absence of Neurod1 several hair cell specific genes such as Myo VIIa, Atoh1, Pou4f3 and Nhlh1 are prematurely expressed with an inverse gradient of apex-to-base progression of hair cell differentiation instead of usual base-to-apex progression (cochlear expression shown with bars in A, A’). In addition, these genes are also expressed ectopically in the differentiating vestibular ganglia near the utricle and saccule. This substantial alteration of gene expression changes the organization of the apical part of the cochlea and results in the formation of ‘intragangliionic hair cells’. Our data and those of others suggest the following interaction of Neurod1 with Neurog1, Atoh1, Sox2 and Fgf8 to regulate inner ear cellular identity (B, B’). We propose that after early and transient activation of Neurod1 by Neurog1 and Atoh1 to differentiate neuron, Neurod1 suppresses Neurog1 to inhibit precursor proliferation and Atoh1 to inhibit hair cell differentiation in neurons. These three way interactions result in formation of neurons with delayed hair cell differentiation. Cross inhibition of Neurog1 and Atoh1 was previously suggested [17, 20] and we suggest that Neurod1 is a key intermediary player. Neurod1 also regulates other cell fate determining genes like Sox2 and Fgf8 which may more directly related to the observed cell fate switch. We suggest that Neurod1 deletion in early embryos disrupts this gene network and, as a consequence, the coordinated sequential neurosensory development of inner ear resulting in the transformation of some surviving neurons into ‘intraganglionic hair cells’ and alteration of the cell type specific differentiation of outer hair cells in the cochlea.
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pone-0011661-g009: Neurod1 regulates neuronal differentiation by suppression of premature hair cell differentiation of neurons possibly interacting with several target genes.In the absence of Neurod1 several hair cell specific genes such as Myo VIIa, Atoh1, Pou4f3 and Nhlh1 are prematurely expressed with an inverse gradient of apex-to-base progression of hair cell differentiation instead of usual base-to-apex progression (cochlear expression shown with bars in A, A’). In addition, these genes are also expressed ectopically in the differentiating vestibular ganglia near the utricle and saccule. This substantial alteration of gene expression changes the organization of the apical part of the cochlea and results in the formation of ‘intragangliionic hair cells’. Our data and those of others suggest the following interaction of Neurod1 with Neurog1, Atoh1, Sox2 and Fgf8 to regulate inner ear cellular identity (B, B’). We propose that after early and transient activation of Neurod1 by Neurog1 and Atoh1 to differentiate neuron, Neurod1 suppresses Neurog1 to inhibit precursor proliferation and Atoh1 to inhibit hair cell differentiation in neurons. These three way interactions result in formation of neurons with delayed hair cell differentiation. Cross inhibition of Neurog1 and Atoh1 was previously suggested [17, 20] and we suggest that Neurod1 is a key intermediary player. Neurod1 also regulates other cell fate determining genes like Sox2 and Fgf8 which may more directly related to the observed cell fate switch. We suggest that Neurod1 deletion in early embryos disrupts this gene network and, as a consequence, the coordinated sequential neurosensory development of inner ear resulting in the transformation of some surviving neurons into ‘intraganglionic hair cells’ and alteration of the cell type specific differentiation of outer hair cells in the cochlea.

Mentions: Neurod1 regulates several genes involved in hair cell differentiation. Atoh1, Pou4f3, Fgf8 and Nhlh1 are prematurely expressed in the apical half of the cochlea in Neurod1 CKO mutants (Fig. 9A,A’) and appear in hair cells within the sensory ganglia of the ear. There is also a transient change in Sox2 expression and in Neurog1 expression. Our results are best compatible with a suggestion that Neurod1 expression in neurosensory precursors suppresses specific downstream genes (Atoh1, Pou4f3, Nhlh1, Fgf8, Sox2) necessary for general neurosensory and specific hair cell differentiation (Fig. 9B,B’). For example, the upregulation of Fgf8 in some ‘outer hair cells’, which may change their fate to ‘inner hair cells’, suggest a more specific function of Neurod1 in regulation of Fgf8. The effect of Neurod1 on Neurog1 is likely due to a direct, intracellular feedback loop (Fig. 9B,B’) and is in line with previous reports of such a feedback loop in olfactory receptor cell development [69]. In contrast, the effect of Neurod1 on Atoh1 expression could be either directly in the same cell as in the cerebellum [26] or could be mediated through an intermediary such as Fgf8, Sox2 or an as yet to be determined factor within or between cells. Further analysis of other developing systems in which Neurod1 and Atoh1 are sequentially expressed or co-expressed, such as the dorsal cochlear nucleus [70] or the enteroendocrine intestine cells [71], are needed to establish generality of this feedback loop beyond the ear and the cerebellum.


Neurod1 suppresses hair cell differentiation in ear ganglia and regulates hair cell subtype development in the cochlea.

Jahan I, Pan N, Kersigo J, Fritzsch B - PLoS ONE (2010)

Neurod1 regulates neuronal differentiation by suppression of premature hair cell differentiation of neurons possibly interacting with several target genes.In the absence of Neurod1 several hair cell specific genes such as Myo VIIa, Atoh1, Pou4f3 and Nhlh1 are prematurely expressed with an inverse gradient of apex-to-base progression of hair cell differentiation instead of usual base-to-apex progression (cochlear expression shown with bars in A, A’). In addition, these genes are also expressed ectopically in the differentiating vestibular ganglia near the utricle and saccule. This substantial alteration of gene expression changes the organization of the apical part of the cochlea and results in the formation of ‘intragangliionic hair cells’. Our data and those of others suggest the following interaction of Neurod1 with Neurog1, Atoh1, Sox2 and Fgf8 to regulate inner ear cellular identity (B, B’). We propose that after early and transient activation of Neurod1 by Neurog1 and Atoh1 to differentiate neuron, Neurod1 suppresses Neurog1 to inhibit precursor proliferation and Atoh1 to inhibit hair cell differentiation in neurons. These three way interactions result in formation of neurons with delayed hair cell differentiation. Cross inhibition of Neurog1 and Atoh1 was previously suggested [17, 20] and we suggest that Neurod1 is a key intermediary player. Neurod1 also regulates other cell fate determining genes like Sox2 and Fgf8 which may more directly related to the observed cell fate switch. We suggest that Neurod1 deletion in early embryos disrupts this gene network and, as a consequence, the coordinated sequential neurosensory development of inner ear resulting in the transformation of some surviving neurons into ‘intraganglionic hair cells’ and alteration of the cell type specific differentiation of outer hair cells in the cochlea.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2908541&req=5

pone-0011661-g009: Neurod1 regulates neuronal differentiation by suppression of premature hair cell differentiation of neurons possibly interacting with several target genes.In the absence of Neurod1 several hair cell specific genes such as Myo VIIa, Atoh1, Pou4f3 and Nhlh1 are prematurely expressed with an inverse gradient of apex-to-base progression of hair cell differentiation instead of usual base-to-apex progression (cochlear expression shown with bars in A, A’). In addition, these genes are also expressed ectopically in the differentiating vestibular ganglia near the utricle and saccule. This substantial alteration of gene expression changes the organization of the apical part of the cochlea and results in the formation of ‘intragangliionic hair cells’. Our data and those of others suggest the following interaction of Neurod1 with Neurog1, Atoh1, Sox2 and Fgf8 to regulate inner ear cellular identity (B, B’). We propose that after early and transient activation of Neurod1 by Neurog1 and Atoh1 to differentiate neuron, Neurod1 suppresses Neurog1 to inhibit precursor proliferation and Atoh1 to inhibit hair cell differentiation in neurons. These three way interactions result in formation of neurons with delayed hair cell differentiation. Cross inhibition of Neurog1 and Atoh1 was previously suggested [17, 20] and we suggest that Neurod1 is a key intermediary player. Neurod1 also regulates other cell fate determining genes like Sox2 and Fgf8 which may more directly related to the observed cell fate switch. We suggest that Neurod1 deletion in early embryos disrupts this gene network and, as a consequence, the coordinated sequential neurosensory development of inner ear resulting in the transformation of some surviving neurons into ‘intraganglionic hair cells’ and alteration of the cell type specific differentiation of outer hair cells in the cochlea.
Mentions: Neurod1 regulates several genes involved in hair cell differentiation. Atoh1, Pou4f3, Fgf8 and Nhlh1 are prematurely expressed in the apical half of the cochlea in Neurod1 CKO mutants (Fig. 9A,A’) and appear in hair cells within the sensory ganglia of the ear. There is also a transient change in Sox2 expression and in Neurog1 expression. Our results are best compatible with a suggestion that Neurod1 expression in neurosensory precursors suppresses specific downstream genes (Atoh1, Pou4f3, Nhlh1, Fgf8, Sox2) necessary for general neurosensory and specific hair cell differentiation (Fig. 9B,B’). For example, the upregulation of Fgf8 in some ‘outer hair cells’, which may change their fate to ‘inner hair cells’, suggest a more specific function of Neurod1 in regulation of Fgf8. The effect of Neurod1 on Neurog1 is likely due to a direct, intracellular feedback loop (Fig. 9B,B’) and is in line with previous reports of such a feedback loop in olfactory receptor cell development [69]. In contrast, the effect of Neurod1 on Atoh1 expression could be either directly in the same cell as in the cerebellum [26] or could be mediated through an intermediary such as Fgf8, Sox2 or an as yet to be determined factor within or between cells. Further analysis of other developing systems in which Neurod1 and Atoh1 are sequentially expressed or co-expressed, such as the dorsal cochlear nucleus [70] or the enteroendocrine intestine cells [71], are needed to establish generality of this feedback loop beyond the ear and the cerebellum.

Bottom Line: Our data suggest that the long noted cross-regulation of Atoh1 expression by Neurog1 might actually be mediated in large part by Neurod1.We suggest that Neurod1 is regulated by both Neurog1 and Atoh1 and provides a negative feedback for either gene.Through this and other feedback, Neurod1 suppresses alternate fates of neurons to differentiate as hair cells and regulates hair cell subtypes.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, University of Iowa, Iowa City, Iowa, United States of America.

ABSTRACT

Background: At least five bHLH genes regulate cell fate determination and differentiation of sensory neurons, hair cells and supporting cells in the mammalian inner ear. Cross-regulation of Atoh1 and Neurog1 results in hair cell changes in Neurog1 mice although the nature and mechanism of the cross-regulation has not yet been determined. Neurod1, regulated by both Neurog1 and Atoh1, could be the mediator of this cross-regulation.

Methodology/principal findings: We used Tg(Pax2-Cre) to conditionally delete Neurod1 in the inner ear. Our data demonstrate for the first time that the absence of Neurod1 results in formation of hair cells within the inner ear sensory ganglia. Three cell types, neural crest derived Schwann cells and mesenchyme derived fibroblasts (neither expresses Neurod1) and inner ear derived neurons (which express Neurod1) constitute inner ear ganglia. The most parsimonious explanation is that Neurod1 suppresses the alternative fate of sensory neurons to develop as hair cells. In the absence of Neurod1, Atoh1 is expressed and differentiates cells within the ganglion into hair cells. We followed up on this effect in ganglia by demonstrating that Neurod1 also regulates differentiation of subtypes of hair cells in the organ of Corti. We show that in Neurod1 conditional mice there is a premature expression of several genes in the apex of the developing cochlea and outer hair cells are transformed into inner hair cells.

Conclusions/significance: Our data suggest that the long noted cross-regulation of Atoh1 expression by Neurog1 might actually be mediated in large part by Neurod1. We suggest that Neurod1 is regulated by both Neurog1 and Atoh1 and provides a negative feedback for either gene. Through this and other feedback, Neurod1 suppresses alternate fates of neurons to differentiate as hair cells and regulates hair cell subtypes.

Show MeSH
Related in: MedlinePlus