Sonic hedgehog antagonists reduce size and alter patterning of the frog inner ear

Abstract

Sonic Hedgehog (Shh) signaling plays a major role in vertebrate development, from regulation of proliferation to the patterning of various organs. In amniotes, Shh affects dorsoventral patterning in the inner ear but affects anteroposterior patterning in teleosts. Currently, it remains unknown the function of Shh in inner ear development in terms of how morphogenesis changes in the sarcopterygian/tetrapod lineage coincide with the evolution of limbs and novel auditory organs in the ear. In this study we used the tetrapod, Xenopus laevis, to test how increasing concentrations of the Shh signal pathway antagonist, Vismodegib, affects ear development. Vismodegib treatment dose dependently alters the development of the ear, hypaxial muscle, and indirectly the Mauthner cell through its interaction with the inner ear afferents. Together, these phenotypes have an effect on escape response. The altered Mauthner cell likely contributes to the increased time to respond to a stimulus. In addition, the increased hypaxial muscle in the trunk likely contributes to the subtle change in animal C-start flexion angle. In the ear, Vismodegib treatment results in decreasing segregation between the gravistatic sensory epithelia as the concentration of Vismodegib increases. Furthermore, at higher doses, there is a loss of the horizontal canal but no enantiomorphic transformation, as in bony fish lacking Shh. Like in amniotes, Shh signaling in frogs affects dorsoventral patterning in the ear, suggesting that auditory sensory evolution in sarcopterygians/tetrapods evolved with a shift of Shh axis specification of the ear.

Hedgehog Signaling Promotes the Proliferation and Subsequent Hair Cell Formation of Progenitor Cells in the Neonatal Mouse Cochlea

“…To further verify the above results, titrated concentrations of Shh protein were used, and the number and diameter of spheres both increased as the concentration of Shh protein increased (Figures 1E,F ). Moreover, another two Hedgehog signaling inhibitors, SANT-1 and vismodegib (Zarei et al, 2017 ), were used to further confirm the effects of Hedgehog inhibition, and the results were consistent with above data (Figure 1E ). These results demonstrated that activation of Hedgehog signaling significantly promoted the cell proliferation and clone-forming ability of postnatal Lgr5+ progenitors and that inhibition of Hedgehog signaling significantly decreased the proliferative ability of Lgr5+ progenitor cells.…”

Effects of Neurod1 Expression on Mouse and Human Schwannoma Cells

“…A model of MB was developed that uses the Atoh1 ‐cre transgene 8 to recombine a floxed stop codon, resulting in expression of constitutively active Smo that reliably develop tumors. These tumors resemble the human sonic hedgehog (Shh)‐dependent MB 30,46,47 by enhancing Shh‐mediated proliferation 48 . Two bHLH transcription factors, Atoh1 and Neurod1, play essential roles in the proliferation and differentiation of granule cell precursors, the cellular source of MB.…”

“…These tumors resemble the human sonic hedgehog (Shh)-dependent MB 30,46,47 by enhancing Shhmediated proliferation. 48 Two bHLH transcription factors, Atoh1 and Neurod1, play essential roles in the proliferation and differentiation of granule cell precursors, the cellular source of MB. Atoh1 regulates Shh signaling in granule cell precursors in the external granule cell layer (EGL) and result in MB formation in the cerebellum.…”

Transcriptome profiles of sturgeon lateral line electroreceptor and mechanoreceptor during regeneration

“…Besides, pax2a was also expressed in the otic region in zebrafish embryo [37]. In addition, as transcription factors/ cofactor or components of signaling transduction, these five genes have ever been reported involving otic morphogenesis through patterning and segmentation [38][39][40][41][42][43]. Specially, zebrafish pax2a was essential for hair cell development [44,45].…”