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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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Inner ear analyses of Bmp4 conditional  embryos.Paint-filled inner ears of control Bmp4loxP/+ (A,G), Foxg1cre/+; Bmp4loxP/Tm1 (B–D,H) and TgPax2cre; Bmp4loxP/Tm1 (E,F) embryos at 11.5 (G,H) and 13.5 dpc (A–F). Inserts in (A)–(F) are ventral views of the cochlear duct. The most malformed inner ears of Foxg1cre/+; Bmp4loxP/Tm1 embryos are shown in (B) and (C), compared to controls (A). In (D), the inner ear is normal except for truncation of the lateral canal (arrows). A mildly (E) and more severely (F) affected inner ear of TgPax2cre; Bmp4loxP/Tm1 embryos. Inner ears of Bmp4loxP/+ (G) and (H) Foxg1cre/+; Bmp4loxP/Tm1 embryos at 11.5 dpc. Arrow in (H) points to the smaller canal pouch in Foxg1cre/+; Bmp4loxP/Tm1 embryos. Orientations in (G) apply to all panels. Scale bars in (F) and (H) apply to (A–E) and (G), respectively.
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pgen-1000050-g002: Inner ear analyses of Bmp4 conditional embryos.Paint-filled inner ears of control Bmp4loxP/+ (A,G), Foxg1cre/+; Bmp4loxP/Tm1 (B–D,H) and TgPax2cre; Bmp4loxP/Tm1 (E,F) embryos at 11.5 (G,H) and 13.5 dpc (A–F). Inserts in (A)–(F) are ventral views of the cochlear duct. The most malformed inner ears of Foxg1cre/+; Bmp4loxP/Tm1 embryos are shown in (B) and (C), compared to controls (A). In (D), the inner ear is normal except for truncation of the lateral canal (arrows). A mildly (E) and more severely (F) affected inner ear of TgPax2cre; Bmp4loxP/Tm1 embryos. Inner ears of Bmp4loxP/+ (G) and (H) Foxg1cre/+; Bmp4loxP/Tm1 embryos at 11.5 dpc. Arrow in (H) points to the smaller canal pouch in Foxg1cre/+; Bmp4loxP/Tm1 embryos. Orientations in (G) apply to all panels. Scale bars in (F) and (H) apply to (A–E) and (G), respectively.

Mentions: The gross anatomy of the Foxg1cre/+; Bmp4loxP/Tm1 inner ears at 13.5 dpc was examined by paint filling the membranous labyrinth. Consistent with the variable Bmp4 expression patterns, the paint-filled Foxg1cre/+; Bmp4loxP/Tm1 specimens also show a range of inner ear phenotypes (Figure 2A–2D). In the most severe cases, there is no discernible ampulla or semicircular canal, and the utricle and saccule are malformed. Only an intact endolymphatic duct is evident in the dorsal region of the inner ear (Figure 2B and 2C; n = 8/14). The remaining specimens are either indistinguishable from Bmp4loxP/+ (n = 3/14) embryos, or display only a lateral canal truncation (Figure 2D; n = 3/14). A percentage of the Bmp4loxP/Tm1 also display similar defects in the lateral canal (n = 5/10). Therefore, this milder phenotype observed in Foxg1cre/+; Bmp4loxP/Tm1 embryos is probably due to insufficiency of Bmp4 caused by the presence of both of the Tm1 and the un-recombined floxed Bmp4 allele rather than an incomplete penetrance of the cre activity. Cochlear ducts of Foxg1cre/+; Bmp4loxP/Tm1 embryos show some variability in length (Figure 2B–2D). We attributed this variability to a slight difference in staging or global growth defects of the ear.


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)

Inner ear analyses of Bmp4 conditional  embryos.Paint-filled inner ears of control Bmp4loxP/+ (A,G), Foxg1cre/+; Bmp4loxP/Tm1 (B–D,H) and TgPax2cre; Bmp4loxP/Tm1 (E,F) embryos at 11.5 (G,H) and 13.5 dpc (A–F). Inserts in (A)–(F) are ventral views of the cochlear duct. The most malformed inner ears of Foxg1cre/+; Bmp4loxP/Tm1 embryos are shown in (B) and (C), compared to controls (A). In (D), the inner ear is normal except for truncation of the lateral canal (arrows). A mildly (E) and more severely (F) affected inner ear of TgPax2cre; Bmp4loxP/Tm1 embryos. Inner ears of Bmp4loxP/+ (G) and (H) Foxg1cre/+; Bmp4loxP/Tm1 embryos at 11.5 dpc. Arrow in (H) points to the smaller canal pouch in Foxg1cre/+; Bmp4loxP/Tm1 embryos. Orientations in (G) apply to all panels. Scale bars in (F) and (H) apply to (A–E) and (G), respectively.
© Copyright Policy
Related In: Results  -  Collection

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

pgen-1000050-g002: Inner ear analyses of Bmp4 conditional embryos.Paint-filled inner ears of control Bmp4loxP/+ (A,G), Foxg1cre/+; Bmp4loxP/Tm1 (B–D,H) and TgPax2cre; Bmp4loxP/Tm1 (E,F) embryos at 11.5 (G,H) and 13.5 dpc (A–F). Inserts in (A)–(F) are ventral views of the cochlear duct. The most malformed inner ears of Foxg1cre/+; Bmp4loxP/Tm1 embryos are shown in (B) and (C), compared to controls (A). In (D), the inner ear is normal except for truncation of the lateral canal (arrows). A mildly (E) and more severely (F) affected inner ear of TgPax2cre; Bmp4loxP/Tm1 embryos. Inner ears of Bmp4loxP/+ (G) and (H) Foxg1cre/+; Bmp4loxP/Tm1 embryos at 11.5 dpc. Arrow in (H) points to the smaller canal pouch in Foxg1cre/+; Bmp4loxP/Tm1 embryos. Orientations in (G) apply to all panels. Scale bars in (F) and (H) apply to (A–E) and (G), respectively.
Mentions: The gross anatomy of the Foxg1cre/+; Bmp4loxP/Tm1 inner ears at 13.5 dpc was examined by paint filling the membranous labyrinth. Consistent with the variable Bmp4 expression patterns, the paint-filled Foxg1cre/+; Bmp4loxP/Tm1 specimens also show a range of inner ear phenotypes (Figure 2A–2D). In the most severe cases, there is no discernible ampulla or semicircular canal, and the utricle and saccule are malformed. Only an intact endolymphatic duct is evident in the dorsal region of the inner ear (Figure 2B and 2C; n = 8/14). The remaining specimens are either indistinguishable from Bmp4loxP/+ (n = 3/14) embryos, or display only a lateral canal truncation (Figure 2D; n = 3/14). A percentage of the Bmp4loxP/Tm1 also display similar defects in the lateral canal (n = 5/10). Therefore, this milder phenotype observed in Foxg1cre/+; Bmp4loxP/Tm1 embryos is probably due to insufficiency of Bmp4 caused by the presence of both of the Tm1 and the un-recombined floxed Bmp4 allele rather than an incomplete penetrance of the cre activity. Cochlear ducts of Foxg1cre/+; Bmp4loxP/Tm1 embryos show some variability in length (Figure 2B–2D). We attributed this variability to a slight difference in staging or global growth defects of the ear.

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