Identification of Synergistic Signals Initiating Inner Ear Development

Abstract

Tissue manipulation experiments in amphibians more than 50 years ago showed that induction of the inner ear requires two signals: a mesodermal signal followed by a neural signal. However, the molecules mediating this process have remained elusive. We present evidence for mesodermal initiation of otic development in higher vertebrates and show that the mesoderm can direct terminal differentiation of the inner ear in rostral ectoderm. Furthermore, we demonstrate the synergistic interactions of the extracellular polypeptide ligands FGF-19 and Wnt-8c as mediators of mesodermal and neural signals, respectively, initiating inner ear development.

Development of the zebrafish inner ear

“…In such embryos, induction of pax8 is delayed by several hours, despite normal timing of gene expression in the hindbrain. These results suggest that prechordal and paraxial cephalic mesendoderm, although not essential for otic induction, are likely to play important roles in this process, a conclusion further supported by recent studies of FGF signaling (Ladher et al, 2000;Phillips et al, 2001). In the next sections, we discuss possible candidate signaling molecules for the inductive signals.…”

“…In addition, periotic mesoderm (presumably expressing Fgf3 and Fgf19) can induce a wide range of otic markers in head ectoderm. Thus Fgf19 interacts synergistically with a variety of other factors expressed in periotic tissues to induce otic differentiation (Ladher et al, 2000).…”

Loss of Fgfr3 leads to excess hair cell development in the mouse organ of Corti

“…At early stages of embryogenesis, Fgfr1, Fgfr2, and several FGFs, including FGF3, FGF8, FGF10, and FGF19, are critical for either the induction of the otic vesicle or the initial development of the sensory epithelium (Mansour et al, 1993;Ladher et al, 2000Ladher et al, , 2005Pirvola et al, 2000Pirvola et al, , 2002Phillips et al, 2001Phillips et al, , 2004Pauley et al, 2003;. At intermediate stages of development, FGF signaling is also important; tissuespecific deletion of Fgfr1 results in severe defects in the development of the auditory sensory epithelium apparently due to a severe reduction in the precursor cells that give rise to the organ of Corti.…”

Genetic interactions underlying otic placode induction and formation

“…Both the hindbrain and mesendoderm have been implicated as signaling sources for otic placode induction (Waddington, 1937;Jacobson, 1966;Chisaka et al, 1992;Moens et al, 1998;Woo and Fraser, 1998;Mendonsa and Riley, 1999), and various FGF signals are expressed in one or both of these tissues in chick, Xenopus, zebrafish, and mouse during otic placode development (Wilkinson et al, 1988(Wilkinson et al, , 1989Niswander and Martin, 1992;Tannahill et al, 1992;Mahmood et al, 1995;McKay et al, 1996;Ladher et al, 2000;Phillips et al, 2001). A role for mesendodermal FGF signaling is seen in chick, in which FGF19-expressing mesoderm can induce Wnt8c expression in adjacent neural tissue, and together these induce expression of otic markers and placode-like structures in tissue culture (Ladher et al, 2000).…”

“…A role for mesendodermal FGF signaling is seen in chick, in which FGF19-expressing mesoderm can induce Wnt8c expression in adjacent neural tissue, and together these induce expression of otic markers and placode-like structures in tissue culture (Ladher et al, 2000). A zebrafish fgf8 mutation, acerebellar (ace), provides evidence for FGF hindbrain signaling (Brand et al, 1996;Reifers et al, 1998;Leger and Brand, 2002).…”