Her9 represses neurogenic fate downstream of Tbx1 and retinoic acid signaling in the inner ear

Abstract

SUMMARYProper spatial control of neurogenesis in the inner ear ensures the precise innervation of mechanotransducing cells and the propagation of auditory and equilibrium stimuli to the brain. Members of the Hairy and enhancer of split (Hes) gene family regulate neurogenesis by inhibiting neuronal differentiation and maintaining neural stem cell pools in non-neurogenic zones. Remarkably, their role in the spatial control of neurogenesis in the ear is unknown. In this study, we identify her9, a zebrafish ortholog of Hes1, as a key gene in regulating otic neurogenesis through the definition of the posterolateral non-neurogenic field. First, her9 emerges as a novel otic patterning gene that represses proneural function and regulates the extent of the neurogenic domain. Second, we place Her9 downstream of Tbx1, linking these two families of transcription factors for the first time in the inner ear and suggesting that the reported role of Tbx1 in repressing neurogenesis is in part mediated by the bHLH transcriptional repressor Her9. Third, we have identified retinoic acid (RA) signaling as the upstream patterning signal of otic posterolateral genes such as tbx1 and her9. Finally, we show that at the level of the cranial otic field, opposing RA and Hedgehog signaling position the boundary between the neurogenic and non-neurogenic compartments. These findings permit modeling of the complex genetic cascade that underlies neural patterning of the otic vesicle.

Fgf and Hh signalling act on a symmetrical pre-pattern to specify anterior and posterior identity in the zebrafish otic placode and vesicle

“…High RA levels appear to specify posterior otic development (in particular Tbx1 expression), and low levels are required for anterior gene expression (including markers of neurogenesis) (Bok et al, 2011). A similar positive regulation of otic tbx1 expression by RA (and negative regulation of neurogenesis) has recently been reported in the zebrafish, although mirror image duplications were not observed (Radosevic et al, 2011). Manipulation of RA signalling is also known to affect earlier stages of zebrafish otic development, but only indirectly; notably, early RA inhibition delays the onset of hindbrain fgf3 expression, and so interferes with otic induction (Hans and Westerfield, 2007).…”

Zebrafish Foxi1 provides a neuronal ground state during inner ear induction preceding the Dlx3b/4b-regulated sensory lineage

“…2P,T). We also examined T-box 1 (tbx1), which is expressed in the non-neurogenic otic territory during placodal and vesicle stages (Piotrowski et al, 2003;Radosevic et al, 2011). We found that Dlx3b/4b-depleted embryos at the 12-somite stage also show a complete absence of tbx1 compared with control embryos or embryos lacking Neurog1 or Foxi1 activity (Fig.…”

Neuron and Sensory Epithelial Cell Fate Is Sequentially Determined by Notch Signaling in Zebrafish Lateral Line Development

“…Mechanisms other than Notch signaling may, however, determine the neuronal and sensory hair fate in zebrafish ear development since, unlike in the mouse inner ear and zebrafish pLL systems, the neuronal and sensory hair precursors are specified at about the same time in the zebrafish ear (Andermann et al, 2002;Abello and Alsina, 2007;Millimaki et al, 2007;Radosevic et al, 2011). Thus, the regulatory mechanisms in pLL development and mouse ear development may share more similarities than those of zebrafish ear and mouse ear development.…”