Site‐specific interactions of neurotrophin‐3 and fibroblast growth factor (FGF2) in the embryonic development of the mouse cochlear nucleus

Abstract

Neurotrophins and FGF2 contribute to formation of the cochlea, but their roles in cochlear nucleus development are unknown. The effects of these factors may differ in the cochlea and cochlear nucleus, which may influence each other's development. It is important to analyze the effects of these factors on cellular structures at well-defined steps in the normal morphogenetic sequence. The present study used immunohistochemistry to localize factors in situ and to test hypotheses about their roles in an in vitro model. Specific antibody staining revealed that TrkC, the NT3 receptor, is present in neural precursors prior to embryonic day E11 until after birth. NT3 appeared in precursor cells during migration (E13-E15) and disappeared at birth. TrkC and NT3 occurred in the same structures, including growing axons, terminals, and their synaptic targets. Thus, NT3 tracks the migration routes and the morphogenetic sequences within a window defined by TrkC. In vitro, the cochlear nucleus anlage was explanted from E11 embryos. Cultures were divided into groups fed with defined medium, with or without FGF2, BDNF, and NT3 supplements, alone or in combinations, for 7 days. When neuroblasts migrated and differentiated, immunostaining was used for locating NT3 and TrkC in the morphogenetic sequence, bromodeoxyuridine for proliferation, and synaptic vesicle protein for synaptogenesis. By time-lapse imaging and quantitative measures, the results support the hypothesis that FGF2 promotes proliferation and migration. NT3 interacts with FGF2 and BDNF to promote neurite outgrowth, fasciculation, and synapse formation. Factors and receptors localize to the structural sites undergoing critical changes.

Interactive roles of fibroblast growth factor 2 and neurotrophin 3 in the sequence of migration, process outgrowth, and axonal differentiation of mouse cochlear ganglion cells

“…Their specific high‐affinity tyrosine kinase receptors (TrkC and Trk B) are expressed in the ear and its innervating sensory neurons (Ernfors et al, 1992; Pirvola et al, 1992, 1994; Ylikoski et al, 1993). Our studies (Hossain et al, 2006) and those of others (e.g., Hafidi et al, 1996; Hafidi, 1999; Tierney et al, 2001) have shown expression of neurotrophins and their receptors in the developing auditory brainstem during embryonic and postnatal periods in mouse, rat, and gerbil.…”

The role of glucocorticoids for spiral ganglion neuron survival

“…Therefore, one question addressed in previous studies is whether age-related loss of hair cells and SGNs are linked. After chemical or mechanical damage of hair cells, SGNs are rapidly lost, which is consistent with findings of trophic support of SGNs by hair cells (Ernfors et al, 1995; Fritzsch et al, 1997; Hossain et al, 2006; Takeno et al, 1998). However, loss of SGNs without associated loss of hair cells is common during aging (Keithley and Feldman, 1979; Keithley et al, 1989; Ryals and Westbrook, 1988; Suzuka and Schuknecht, 1988; White et al, 2000).…”

Changes in Sef Levels Influence Auditory Brainstem Development and Function

“…In vitro, Sef overexpression induces apoptosis, whereas knockdown of Sef promotes cell migration in response to FGF ligand, but in vivo roles for Sef have not yet been described (Darby et al, 2006;Kovalenko et al, 2006). FGF2 independently affects both the proliferation and migration of cochlear nucleus precursors in vitro (Zhou et al, 1996;Hossain et al, 2006), whereas FGF8 contributes to tissue morphogenesis, proliferation, and survival in the hindbrain but is surprisingly dispensible for specific cell fate decisions here (Foucher et al, 2006). Similarly, there are no obvious changes in gene expression in Sef mutant embryos, and the effects of Sef overexpression could be explained either by decreased proliferation and/or increased cell death.…”

“…The molecular heterogeneity of the rhombic lip suggests that secreted signals may regulate cell fate decisions here (Timmer et al, 2002;Landsberg et al, 2005). Indeed, FGF2 induces proliferation and migration of cochlear nucleus precursors from the rhombic lip in vitro (Zhou et al, 1996;Hossain et al, 2006). Thus, changes in FGF signaling could affect rhombic lip development and may result in changes in sound perception.…”