Making connections in the inner ear: Recent insights into the development of spiral ganglion neurons and their connectivity with sensory hair cells

Highlights

• New insights into the origins of the SGNs: the reemergence of the neural crest.

• New insights into the specification of CVG neuroblasts.

• Mechanisms of hair cell innervation by SGN peripheral axons.

• Tonotopic specializations of the SGNs.

Abstract

In mammals, auditory information is processed by the hair cells (HCs) located in the cochlea and then rapidly transmitted to the CNS via a specialized cluster of bipolar afferent connections known as the spiral ganglion neurons (SGNs). Although many anatomical aspects of SGNs are well described, the molecular and cellular mechanisms underlying their genesis, how they are precisely arranged along the cochlear duct, and the guidance mechanisms that promote the innervation of their hair cell targets are only now being understood. Building upon foundational studies of neurogenesis and neurotrophins, we review here new concepts and technologies that are helping to enrich our understanding of the development of the nervous system within the inner ear.

Introduction

The mammalian cochlea is a complex coiled organ composed of an array of cell types precisely arranged so that sound stimuli can be accurately transmitted from the outside world into the brain (Fig. 1). The two major sensory cell types of the peripheral auditory system are the mechanically sensitive hair cells (HCs), and their afferent partners, the spiral ganglion neurons (SGNs). The HCs are located within the sensory domain of the cochlear epithelium, known as the organ of Corti (OC), and reside with a variety of supporting cell and non-sensory epithelial cell types. The SGNs are specialized bipolar neurons that extend peripheral axons (sometimes termed “dendrites”) that couple to HCs at ribbon-type synapses, and centrally projecting axons that bifurcate, sending individual processes into the dorsal and ventral cochlear nuclei (DCN and VCN). An amazing and relatively unexplored aspect of this auditory relay system is the set of developmental mechanisms used to encode a frequency gradient along the longitudinal (or “tonotopic”) axis of the spiraling cochlea: HCs and SGNs at the base of the cochlea respond to high-frequency sounds, whereas those located progressively toward the apex transmit lower-frequency sounds.

How is this remarkable sensory system established during development? The molecular mechanisms of hair cell and supporting cell development within the OC have been reviewed extensively [1], [2], [3], [4], [5] and will not be discussed here. Rather, our objective is to examine several recent advances in the development of the SGNs and how they traverse the complex anatomy of the developing cochlea before making functional connections with HCs. Several other excellent reviews have focused on these matters [6], [7], [8], but additional findings have emerged that have started to close the knowledge gap on several issues. First, we will start at the headwaters of SGN development where new light has been shed on the neuroblasts that give rise to the SGNs (see Section 3). Next, we will discuss the complex morphogenetic movements made by the SGNs along the lengthening cochlear duct and their maturation into bipolar neurons (Section 4). Subsequently, we describe several new findings on the accurate extension of SGN peripheral axons into the developing cochlear epithelium (Section 5). Finally we will discuss new insights on the tonotopic arrangement of the SGNs (Section 6), which may provide important insights into how physiological diversity along the frequency axis is generated. The scope of this review does not include important advances made in models of sensorineural deafness where the survival and maintenance of postnatal SGNs is of central focus (please see [9], [10]), and does not include extensive discussion of the roles of neurotrophins (please see [11], [12]).