BMP4 signaling is involved in the generation of inner ear sensory epithelia

Abstract

BackgroundThe robust expression of BMP4 in the incipient sensory organs of the inner ear suggests possible roles for this signaling protein during induction and development of auditory and vestibular sensory epithelia. Homozygous BMP4-/- animals die before the inner ear's sensory organs develop, which precludes determining the role of BMP4 in these organs with simple gene knockout experiments.ResultsHere we use a chicken otocyst culture system to perform quantitative studies on the development of inner ear cell types and show that hair cell and supporting cell generation is remarkably reduced when BMP signaling is blocked, either with its antagonist noggin or by using soluble BMP receptors. Conversely, we observed an increase in the number of hair cells when cultured otocysts were treated with exogenous BMP4. BMP4 treatment additionally prompted down-regulation of Pax-2 protein in proliferating sensory epithelial progenitors, leading to reduced progenitor cell proliferation.ConclusionOur results implicate BMP4 in two events during chicken inner ear sensory epithelium formation: first, in inducing the switch from proliferative sensory epithelium progenitors to differentiating epithelial cells and secondly, in promoting the differentiation of hair cells within the developing sensory epithelia.

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

“…Consistent with the gene expression changes, the long-term effects are disruption of the crista structure in addition to the loss of sensory hair cells. Taken together, our results suggest that Bmp4 has a global role in organizing the structure of the crista into sensory and non-sensory domains rather than just promoting or inhibiting hair cell fate [24],[25]. This organizing role could involve interacting with the Notch signaling pathway in cell type specification.…”

Disrupting the Interaction between Retinoblastoma Protein and Raf-1 Leads to Defects in Progenitor Cell Proliferation and Survival during Early Inner Ear Development

“…The antibodies were diluted in blocking solution to analyze the levels of Raf-1 kinases (1∶500, BD Transduction Laboratories, Franklin Lakes, NJ), pERK/ERK (1∶500, Bioworld Technology, Louis Park, MN), pRb (1∶1000, Cell Signaling Technology, Danvers, MA), cleaved Caspase-3 (1∶500, Cell Signaling Technology, Danvers, MA), and β-actin (1∶5000, Sigma, St. Louis, MO). All the antibodies involved in our study were produced against highly conserved proteins from chick to mammal and the majority have been confirmed by other chicken studies [2], [16]. Unbound primary antibodies were removed by four washes of 15 min each in TBS-T at room temperature.…”

The Genetics of Hair Cell Development and Regeneration

“…Manipulation of the BMP, FGF, Shh and Wnt signaling pathways can all alter the numbers of hair cells in inner ear sensory organs (Driver et al 2008, Hayashi et al 2008, Huh et al 2012, Kamaid et al 2010, Li et al 2005, Pirvola et al 2002, Pujades et al 2006, Stevens et al 2003), although it is far less clear to what extent these effects are due to the direct regulation of Atoh1 transcription, to indirect transcriptional regulation by induction of other factors that can themselves regulate Atoh1 , or post-translational modification of the Atoh1 protein (Mulvaney & Dabdoub 2012). Far more attention has focused on regions of the Atoh1 locus that regulate its transcription, particularly on two enhancer elements located 3.4kb downstream of the Atoh1 coding region (Figure 2; Helms et al 2000).…”