Biphasic functions for the GDNF-Ret signaling pathway in chemosensory neuron development and diversification

Abstract

SignificanceWhile knowledge of signaling mechanisms orchestrating the development and diversification of peripheral somatosensory neurons is extensive, our understanding of the mechanisms controlling chemosensory neuron specification remains rudimentary. Lingually projecting sensory neurons of the geniculate ganglion are receptive to the five taste qualities, as well as temperature and tactile stimuli, but the mechanisms responsible for the diversification of the unique subpopulations that respond to one, or several, of these stimuli remain unknown. Here we demonstrate that the GDNF-Ret signaling pathway exerts a unique, dual function in peripheral taste system development and postnatal function. Ret acts embryonically to regulate the expression of the chemosensory master regulator Phox2b, thus inducing chemosensory differentiation, while postnatally acting to specify a molecularly unique subpopulation of lingual mechanoreceptors.

Role of TrkB-signaling in taste development and function.

“…Consistently, Mafb+ neurons tend to express lower levels of TrkB than other Phox2b+ neurons in the geniculate ganglion (Dvoryanchikov et al, 2017). These remaining neurons could also be a subpopulation supported by GDNF-signaling via the Ret receptor (Donnelly et al, 2018), rather than TrkB.…”

“…Another example in these same neurons of a developmentally critical gene changing roles during development, is the growth factor receptor, Ret (27). Ret regulates expression of the transcription factor, Phox2b, embryonically, but later identifies a subset of adult Ret expressing neurons that are likely somatosensory in function (Donnelly et al, 2018). The role of TrkB in adulthood may be to regulate plasticity and branching characteristics for a subset set of oral sensory geniculate neurons (TrkB-expressing ), but could also regulate taste function in this same neuron subset.…”

“…For example, the growth factor receptor, Ret, is expressed in both TrkB+ and TrkB-neurons, which further divides oral sensory neurons into Ret+TrkB+,Ret+TrkB-,Ret-TrkB+, etc. (Donnelly et al, 2018). Using a combination of factors to specify neuron subtypes permits a smaller number of factors to orchestrate the development of a larger number of neuron subtypes (i.e.…”

“…One is that these few remaining nerve fibers were innervating locations previously occupied by a taste bud. Alternatively, these remaining neurons may be non-taste, and could belong instead to a small somatosensory population in the geniculate ganglion that innervate the oral cavity (Donnelly et al, 2018;Yokota & Bradley, 2016.…”

“…In the geniculate ganglion, this is specific to oral sensory and excludes the somatosensory neurons that innervate the outer ear via the auricular nerve (Ohman-Gault et al, 2017). These oral sensory neurons are mostly gustatory, but also include somatosensory fibers (Donnelly, Shah, Mistretta, Bradley, & Pierchala, 2018;Dvoryanchikov et al, 2017;Kumari et al, 2015;Kumari et al, 2017). However, most of the somatosensory neurons innervating the tongue arise from the trigeminal ganglion.…”