A network of growth and transcription factors controls neuronal differentation and survival in the developing ear

Abstract

Inner ear neurons develop from the otic placode and connect hair cells with central neurons in auditory brain stem nuclei. Otic neurogenesis is a developmental process which can be separated into different cellular states that are characterized by a distinct combination of molecular markers. Neurogenesis is highly regulated by a network of extrinsic and intrinsic factors, whose participation in auditory neurogenesis is discussed. Trophic factors include the fibroblast growth factor, neurotrophins and insulin-like peptide families. The expression domains of transcription factor families and their roles in the regulation of intracellular signaling pathways associated with neurogenesis are also discussed. Understanding and defining the key factors and gene networks in the development and function of the inner ear represents an important step towards defeating deafness. KEY WORDS: otic neurogenesis, IGF-I, FGF, inner ear, auditory ganglion, cochlear microarray Otic neurogenesisThe inner ear develops from the otic placode, an ectodermal patch located close to the neural tube that invaginates to form a transitory structure, the otic cup. This cup subsequently closes and pinches off from the ectoderm to generate the otic vesicle ( Figure 1). The otic vesicle is an autonomous structure that contains the information required to generate most of the cell types and structures of the adult inner ear (Bissonnette and Fekete, 1996;Bever et al., 2003; reviewed in Varela-Nieto et al., 2004). The mammalian inner ear is composed of six distinct sensory organs: the three cristae of the semicircular canal, the two maculae of the saccule and utricle and the organ of Corti in the cochlea. The cristae and the maculae are vestibular organs, whereas the organ of Corti is the organ of hearing (reviewed in Moller, 2006). The inner ear cochlear ganglion is formed by bipolar neurons that connect the peripheral sensory receptors or hair cells with central neurons in auditory brain stem nuclei. The correct organogenesis of the inner ear involves a dynamic balance of cell proliferation, differentiation, survival and death, processes that are tightly regulated by a network of extrinsic and intrinsic factors (Frago et al., 2000;Varela-Nieto et al., 2003 andLeon et al., 2004).The process of otic neurogenesis can be separated into different cellular states, each characterized by a distinct combination of molecular markers (summarized in Figure 1A). The first Int. J. Dev. Biol. 51: 557-570 (2007) doi: 10.1387/ijdb.072373hs visible output of otic neurogenesis is the delamination of neural cells (otic neuroblasts) from the otic cup (Fig. 1B). These neuroblasts are committed to generate otic neurons and they populate the cochleo-vestibular ganglion (CVG). This ganglion is generated from a region of the otic vesicle epithelium denominated the prospective neural-sensorial domain and that is defined by the domain in which Ngn1 and Deltal1 are co-expressed at early stages (Adam et al., 1998;Abu-Elmagd et al., 2001). It is believed that both n...

The ATP-dependent chromatin remodeling enzyme CHD7 regulates pro-neural gene expression and neurogenesis in the inner ear

“…After acquisition of neural competence and expression of proneural genes, cells within the anteroventral region of the otocyst delaminate and proliferate to form neurons of the statoacoustic (future vestibulo-cochlear) ganglion Fritzsch et al, 1999;Sanchez-Calderon et al, 2007). After delamination, ganglionic neuroblasts continue to proliferate and later differentiate into bipolar neurons that send projections to the brain and to inner ear sensory end organs (Fritzsch et al, 2005).…”

“…After delamination, ganglionic neuroblasts continue to proliferate and later differentiate into bipolar neurons that send projections to the brain and to inner ear sensory end organs (Fritzsch et al, 2005). As bipolar neurons develop, pro-neural fate markers are downregulated and genes that are essential for neuronal survival and extension, including TrkB and TrkC neurotrophin receptors, are expressed (Pirvola and Ylikoski, 2003;Sanchez-Calderon et al, 2007). Non-ganglionic progenitors in the neurogenic region of the otic epithelium are fated to develop into cells that occupy the sensory epithelium of the vestibular maculae (Raft et al, 2007).…”

The molecular biology of ear development - "Twenty years are nothing"

“…Specifically, otic neurons are known to depend on FGFs, the NGF-related neurotrophins BDNF and NT-3 and Insulin Growth Factor-1 (IGF-1) as major signalling systems for survival. Recent advances on the analysis of the mechanisms of action of those factors are reviewed in depth by Sánchez-Calderón et al, 2007. All neurotrophins bind to p75 NTR , which also interacts with Trk receptors to modulate ligand binding specificity, affinity and function of neurotrophins in certain cell types (Bibel et al, 1999).…”

“…In summary, there is a great interest in understanding mechanisms and effects of those three families of trophic factors (Fgfs, NTs and IGFs) that are known to maintain neuronal survival during the development of the ear and that are also the basis for understanding and preventing degenerative processes that occur during adult life. While NTs clearly have the lead role in otic neuron survival and also in fibre guidance (Tessarollo et al, 2004), other factors complement and partially substitute for this function (Sánchez-Calderón et al, 2007).…”

Insulin Receptor Substrate 2 (IRS2)-Deficient Mice Show Sensorineural Hearing Loss That Is Delayed by Concomitant Protein Tyrosine Phosphatase 1B (PTP1B) Loss of Function

“…Similarly, Igf1 -/-mice exhibit delayed myelination (17,18), severe sensorineural deafness (19,20) and progressive blindness (21). The cochlea of IGF-1-deficient mice presents an abnormal tectorial membrane, increased neuronal apoptosis, poor myelination of nerve fibers (22,23) and impaired activation of protein kinase B (PKB; AKT) and rapid accelerated fibrosarcoma (RAF) kinases (24). Irs2 -/-mice also show impaired brain growth (25), defects in myelination (26) and increased apoptosis in the retina (27).…”