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Bmp4 is essential for the formation of the vestibular apparatus that detects angular head movements.

Chang W, Lin Z, Kulessa H, Hebert J, Hogan BL, Wu DK - PLoS Genet. (2008)

Bottom Line: Angular head movements in vertebrates are detected by the three semicircular canals of the inner ear and their associated sensory tissues, the cristae.Mechanisms involved in the formation of sensory organs of the vertebrate inner ear are thought to be analogous to those regulating sensory bristle formation in Drosophila.Our results suggest that, in comparison to sensory bristles, crista formation within the inner ear requires an additional step of sensory and non-sensory fate specification.

View Article: PubMed Central - PubMed

Affiliation: National Institute on Deafness and Other Communication Disorders, NIH, Rockville, Maryland, United States of America.

ABSTRACT
Angular head movements in vertebrates are detected by the three semicircular canals of the inner ear and their associated sensory tissues, the cristae. Bone morphogenetic protein 4 (Bmp4), a member of the Transforming growth factor family (TGF-beta), is conservatively expressed in the developing cristae in several species, including zebrafish, frog, chicken, and mouse. Using mouse models in which Bmp4 is conditionally deleted within the inner ear, as well as chicken models in which Bmp signaling is knocked down specifically in the cristae, we show that Bmp4 is essential for the formation of all three cristae and their associated canals. Our results indicate that Bmp4 does not mediate the formation of sensory hair and supporting cells within the cristae by directly regulating genes required for prosensory development in the inner ear such as Serrate1 (Jagged1 in mouse), Fgf10, and Sox2. Instead, Bmp4 most likely mediates crista formation by regulating Lmo4 and Msx1 in the sensory region and Gata3, p75Ngfr, and Lmo4 in the non-sensory region of the crista, the septum cruciatum. In the canals, Bmp2 and Dlx5 are regulated by Bmp4, either directly or indirectly. Mechanisms involved in the formation of sensory organs of the vertebrate inner ear are thought to be analogous to those regulating sensory bristle formation in Drosophila. Our results suggest that, in comparison to sensory bristles, crista formation within the inner ear requires an additional step of sensory and non-sensory fate specification.

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Ectopic expression of Noggin down-regulates crista-associated genes in chicken inner ears.Inner ears were electroporated with pNoggin (A,C,E) and pIRES-Gfp (B,D,F) at E3.5 and harvested 14 hrs later. (A–A”) Adjacent sections probed for Gfp (A), Msx1 (A'), and Bmp4 (A”) transcripts. Msx1 (A') expression is abolished in the electoporated (A), Bmp4-positive anterior crista region (A”, ac), whereas Bmp4 expression is not affected (A”). Msx1 expression is reduced in the mesenchymal region (A', arrowheads). (C–C”) Adjacent sections showing the absence of Lmo4 (C') in the electroporated (C), Sox2-positive anterior crista region (C”, arrows). (E–E”) Adjacent sections probed for Gfp (E), Gata3 (E'), and Ser1 (E”) transcripts. (E') Gata3 expression is down-regulated in the anterior crista (arrows) as well as the surrounding mesenchyme (arrowheads), but Ser1 expression is not changed (E”). (B,D,F) None of these gene expression patterns are affected in specimens electroporated with the pIRES-Gfp. Abbreviations: cvg, cochleovestibular ganglion. Scale bar in (F”) equals 100 μm and applies to all panels.
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pgen-1000050-g006: Ectopic expression of Noggin down-regulates crista-associated genes in chicken inner ears.Inner ears were electroporated with pNoggin (A,C,E) and pIRES-Gfp (B,D,F) at E3.5 and harvested 14 hrs later. (A–A”) Adjacent sections probed for Gfp (A), Msx1 (A'), and Bmp4 (A”) transcripts. Msx1 (A') expression is abolished in the electoporated (A), Bmp4-positive anterior crista region (A”, ac), whereas Bmp4 expression is not affected (A”). Msx1 expression is reduced in the mesenchymal region (A', arrowheads). (C–C”) Adjacent sections showing the absence of Lmo4 (C') in the electroporated (C), Sox2-positive anterior crista region (C”, arrows). (E–E”) Adjacent sections probed for Gfp (E), Gata3 (E'), and Ser1 (E”) transcripts. (E') Gata3 expression is down-regulated in the anterior crista (arrows) as well as the surrounding mesenchyme (arrowheads), but Ser1 expression is not changed (E”). (B,D,F) None of these gene expression patterns are affected in specimens electroporated with the pIRES-Gfp. Abbreviations: cvg, cochleovestibular ganglion. Scale bar in (F”) equals 100 μm and applies to all panels.

Mentions: Electroporation of pSmad6 results in the down-regulation of genes that are eventually associated with the non-sensory, septum cruciatum, such as Gata3 (Figure 5D'; n = 10/10) and p75Ngfr (Figure 5F'; n = 10/13), whereas expression levels of genes associated with the sensory regions such as Sox2 (n = 0/6), Fgf10 (n = 0/6), Lmo4 (n = 0/9) and Ser1 (n = 0/5) are not affected (Figure 5D”,F”, and data not shown). Electroporation of a control vector expressing Gfp alone does not result in gene expression changes in most cases (Figure 5E–E”,G–G”; n = 42/44). Down-regulation of Msx1 in response to pSmad6 is variable (n = 7/14; data not shown), but quite consistently seen in response to pNoggin (Figure 6A'; n = 6/6). The expression of Lmo4, which is associated with both sensory and non-sensory regions, is down-regulated by pNoggin (Figure 6C'; n = 11/11), but this is not observed with pSmad6 (n = 9; data not shown). Since Noggin is a secreted molecule, down-regulation of Gata3 and Msx1 in the mesenchyme near the site of electroporation is also observed (Figure 6A',B',E',F', double arrowheads; n = 6/6). Genes that are not down-regulated by pSmad6, such as Bmp4, Fgf10, Ser1 and Sox2, remain unaffected by pNoggin treatments (Figure 6A”,C”,E”; data not shown). Electroporation of a control vector, pIRES-Gfp, usually causes no change in these gene expression patterns (Figure 6B, 6D, 6F; n = 26/28).


Bmp4 is essential for the formation of the vestibular apparatus that detects angular head movements.

Chang W, Lin Z, Kulessa H, Hebert J, Hogan BL, Wu DK - PLoS Genet. (2008)

Ectopic expression of Noggin down-regulates crista-associated genes in chicken inner ears.Inner ears were electroporated with pNoggin (A,C,E) and pIRES-Gfp (B,D,F) at E3.5 and harvested 14 hrs later. (A–A”) Adjacent sections probed for Gfp (A), Msx1 (A'), and Bmp4 (A”) transcripts. Msx1 (A') expression is abolished in the electoporated (A), Bmp4-positive anterior crista region (A”, ac), whereas Bmp4 expression is not affected (A”). Msx1 expression is reduced in the mesenchymal region (A', arrowheads). (C–C”) Adjacent sections showing the absence of Lmo4 (C') in the electroporated (C), Sox2-positive anterior crista region (C”, arrows). (E–E”) Adjacent sections probed for Gfp (E), Gata3 (E'), and Ser1 (E”) transcripts. (E') Gata3 expression is down-regulated in the anterior crista (arrows) as well as the surrounding mesenchyme (arrowheads), but Ser1 expression is not changed (E”). (B,D,F) None of these gene expression patterns are affected in specimens electroporated with the pIRES-Gfp. Abbreviations: cvg, cochleovestibular ganglion. Scale bar in (F”) equals 100 μm and applies to all panels.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC2274953&req=5

pgen-1000050-g006: Ectopic expression of Noggin down-regulates crista-associated genes in chicken inner ears.Inner ears were electroporated with pNoggin (A,C,E) and pIRES-Gfp (B,D,F) at E3.5 and harvested 14 hrs later. (A–A”) Adjacent sections probed for Gfp (A), Msx1 (A'), and Bmp4 (A”) transcripts. Msx1 (A') expression is abolished in the electoporated (A), Bmp4-positive anterior crista region (A”, ac), whereas Bmp4 expression is not affected (A”). Msx1 expression is reduced in the mesenchymal region (A', arrowheads). (C–C”) Adjacent sections showing the absence of Lmo4 (C') in the electroporated (C), Sox2-positive anterior crista region (C”, arrows). (E–E”) Adjacent sections probed for Gfp (E), Gata3 (E'), and Ser1 (E”) transcripts. (E') Gata3 expression is down-regulated in the anterior crista (arrows) as well as the surrounding mesenchyme (arrowheads), but Ser1 expression is not changed (E”). (B,D,F) None of these gene expression patterns are affected in specimens electroporated with the pIRES-Gfp. Abbreviations: cvg, cochleovestibular ganglion. Scale bar in (F”) equals 100 μm and applies to all panels.
Mentions: Electroporation of pSmad6 results in the down-regulation of genes that are eventually associated with the non-sensory, septum cruciatum, such as Gata3 (Figure 5D'; n = 10/10) and p75Ngfr (Figure 5F'; n = 10/13), whereas expression levels of genes associated with the sensory regions such as Sox2 (n = 0/6), Fgf10 (n = 0/6), Lmo4 (n = 0/9) and Ser1 (n = 0/5) are not affected (Figure 5D”,F”, and data not shown). Electroporation of a control vector expressing Gfp alone does not result in gene expression changes in most cases (Figure 5E–E”,G–G”; n = 42/44). Down-regulation of Msx1 in response to pSmad6 is variable (n = 7/14; data not shown), but quite consistently seen in response to pNoggin (Figure 6A'; n = 6/6). The expression of Lmo4, which is associated with both sensory and non-sensory regions, is down-regulated by pNoggin (Figure 6C'; n = 11/11), but this is not observed with pSmad6 (n = 9; data not shown). Since Noggin is a secreted molecule, down-regulation of Gata3 and Msx1 in the mesenchyme near the site of electroporation is also observed (Figure 6A',B',E',F', double arrowheads; n = 6/6). Genes that are not down-regulated by pSmad6, such as Bmp4, Fgf10, Ser1 and Sox2, remain unaffected by pNoggin treatments (Figure 6A”,C”,E”; data not shown). Electroporation of a control vector, pIRES-Gfp, usually causes no change in these gene expression patterns (Figure 6B, 6D, 6F; n = 26/28).

Bottom Line: Angular head movements in vertebrates are detected by the three semicircular canals of the inner ear and their associated sensory tissues, the cristae.Mechanisms involved in the formation of sensory organs of the vertebrate inner ear are thought to be analogous to those regulating sensory bristle formation in Drosophila.Our results suggest that, in comparison to sensory bristles, crista formation within the inner ear requires an additional step of sensory and non-sensory fate specification.

View Article: PubMed Central - PubMed

Affiliation: National Institute on Deafness and Other Communication Disorders, NIH, Rockville, Maryland, United States of America.

ABSTRACT
Angular head movements in vertebrates are detected by the three semicircular canals of the inner ear and their associated sensory tissues, the cristae. Bone morphogenetic protein 4 (Bmp4), a member of the Transforming growth factor family (TGF-beta), is conservatively expressed in the developing cristae in several species, including zebrafish, frog, chicken, and mouse. Using mouse models in which Bmp4 is conditionally deleted within the inner ear, as well as chicken models in which Bmp signaling is knocked down specifically in the cristae, we show that Bmp4 is essential for the formation of all three cristae and their associated canals. Our results indicate that Bmp4 does not mediate the formation of sensory hair and supporting cells within the cristae by directly regulating genes required for prosensory development in the inner ear such as Serrate1 (Jagged1 in mouse), Fgf10, and Sox2. Instead, Bmp4 most likely mediates crista formation by regulating Lmo4 and Msx1 in the sensory region and Gata3, p75Ngfr, and Lmo4 in the non-sensory region of the crista, the septum cruciatum. In the canals, Bmp2 and Dlx5 are regulated by Bmp4, either directly or indirectly. Mechanisms involved in the formation of sensory organs of the vertebrate inner ear are thought to be analogous to those regulating sensory bristle formation in Drosophila. Our results suggest that, in comparison to sensory bristles, crista formation within the inner ear requires an additional step of sensory and non-sensory fate specification.

Show MeSH
Related in: MedlinePlus