Selective disruption of trigeminal sensory neurogenesis and differentiation in a mouse model of 22q11.2 deletion syndrome.

Corey A. Bryan,Thomas M. Maynard,Beverly A. Karpinski,Sally A. Moody,Anthony-Samuel LaMantia,Norman H. Lee,Anelia Horvath,Gelila Yitsege

doi:10.1242/dmm.047357

Abstract

ABSTRACT22q11.2 Deletion Syndrome (22q11DS) is a neurodevelopmental disorder associated with cranial nerve anomalies and disordered oropharyngeal function, including pediatric dysphagia. Using the LgDel 22q11DS mouse model, we investigated whether sensory neuron differentiation in the trigeminal ganglion (CNgV), which is essential for normal orofacial function, is disrupted. We did not detect changes in cranial placode cell translocation or neural crest migration at early stages of LgDel CNgV development. However, as the ganglion coalesces, proportions of placode-derived LgDel CNgV cells increase relative to neural crest cells. In addition, local aggregation of placode-derived cells increases and aggregation of neural crest-derived cells decreases in LgDel CNgV. This change in cell-cell relationships was accompanied by altered proliferation of placode-derived cells at embryonic day (E)9.5, and premature neurogenesis from neural crest-derived precursors, reflected by an increased frequency of asymmetric neurogenic divisions for neural crest-derived precursors by E10.5. These early differences in LgDel CNgV genesis prefigure changes in sensory neuron differentiation and gene expression by postnatal day 8, when early signs of cranial nerve dysfunction associated with pediatric dysphagia are observed in LgDel mice. Apparently, 22q11 deletion destabilizes CNgV sensory neuron genesis and differentiation by increasing variability in cell-cell interaction, proliferation and sensory neuron differentiation. This early developmental divergence and its consequences may contribute to oropharyngeal dysfunction, including suckling, feeding and swallowing disruptions at birth, and additional orofacial sensory/motor deficits throughout life.

Highlights

Using Leafcutter software (Li et al, 2018), we found significant enrichment of differential splicing in LgDel CNgV, including four genes associated with neuronal morphology and proliferation (Fig. S1B): Adgrg1 (Salzman et al, 2016) associated with polymicrogyria; adgrv1 (McMillan et al, 2002) with Usher Syndrome; L1-related Ig-like Nfasc (Ebel et al, 2014) with neural development and demyelinating neuropathies; and Cd151 was implicated in trigeminal placode identity and placodal sensory neuron differentiation (McCabe et al, 2004)
Proportions of neural crest- versus placode-associated progenitors, cell-cell interactions and modes, as well as the frequency of neurogenic divisions, diverge during early CNgV development in the LgDel mouse 22q11.2 DS model. These changes result in heterochronic neurogenesis from primarily neural crest progenitors, and prefigure altered early postnatal CNgV sensory neuron differentiation (Fig. 8)
The deletion of 22q11 apparently results in altered sizes and levels of gene expression for molecularly defined classes of CNgV sensory neurons, with many of these changes focused on presumed neural crest-derived nociceptive neurons (Fig. 8)

Summary

Introduction

Appropriate genesis and differentiation of cranial sensory neurons is essential for homeostatic behaviors that must be in place at birth in. Handling Editor: Pamela Hoodless Received 1 September 2020; Accepted 9 March 2021 all mammals The sensory information these neurons transduce and relay, those in the trigeminal ganglion (CNgV), guide key newborn behaviors, including breathing, as well as suckling, feeding and swallowing (S/F/S; Maynard et al, 2020b). We analyzed CNgV development from midgestation through early postnatal life in LgDel mice, a genomically accurate 22q11DS model, in which pups have several deficits that parallel disrupted S/F/S (Karpinski et al, 2016, 2014; Welby et al, 2020; Yitsege et al, 2020)

Methods

Results

Conclusion