Bmp4 Is Essential for the Formation of the Vestibular Apparatus that Detects Angular Head Movements

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-β), 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.

IdGene Regulation and Function in the Prosensory Domains of the Chicken Inner Ear: A Link between Bmp Signaling andAtoh1

“…Focal electroporation of HH20-HH21 otic vesicles was performed in ovo, using a method modified from Chang et al (2008). The cathode consisted of a 0.3 mm diameter Pt tip attached to a handle and the anode was a 0.5 mm diameter Pt electrode that was placed underneath the embryo.…”

“…For ear development, Chang et al (2008) had proposed a model where a sequential action of Bmp4 is required first for prosensory development, and second for the specification of supporting cells and the nonsensory elements of the sensory organs. Chang et al (2008) suggest that persisting Bmp signaling in the supporting cell layer and in the edges of the patches contribute to specify supporting and nonsensory cell fates respectively. Supporting cells are under the effects of Bmp signaling and they express Bmptarget genes like Msx1 and Lmo4 (Chang et al, 2008), but they exhibit low Id expression.…”

“…This function is reminiscent of that of Bmps in other neural progenitors and stem cells where they maintain the pluripotency of embryonic stem cells and have negative effects on neural differentiation (Varga and Wrana, 2005;Chen and Panchision, 2007). In addition, Bmp signaling is also necessary for the specification of nonsensory and supporting cell fates from the prosensory domain (Chang et al, 2008). These diverse and sometimes paradoxical functions may be related to the specific regulation of the Bmp response in different cellular states and contexts.…”

“…Several Bmp ligands are expressed in the developing ear where they map to prosensory patches and sensory organs in several animal species Morsli et al, 1998). The functions of Bmp signaling in the inner ear are probably multiple and span across different developmental stages (Chang et al, 1999(Chang et al, , 2002(Chang et al, , 2008Gerlach et al, 2000;Li et al, 2005;Pujades et al, 2006). With respect to sensory organ development, Bmps are known to prevent Atoh1 expression and to maintain the undifferentiated state of sensory progenitors (Pujades et al, 2006).…”

Notch signaling is required for the generation of hair cells and supporting cells in the mammalian inner ear

“…However, ectopic expression of SOX2 in cochlear explants does not lead to new sensory regions (10), raising the question as to whether SOX2 is sufficient for sensory specification. Other factors shown to be involved in prosensory development in the inner ear include Wnt, Bmp, Fgf, and Notch signaling pathways (11)(12)(13)(14)(15)(16)(17)(18)(19). Which of these signaling pathways is required for sensory progenitor specification, rather than for sensory progenitor maintenance and/or other aspects of sensory development, is not known.…”