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

Abstract

22q11.2 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 asked 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. As the ganglion coalesces, however, 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 E9.5, and premature neurogenesis from neural crest-derived precursors, reflected by 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 P8, 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.

Loss of Elp1 disrupts trigeminal ganglion neurodevelopment in a model of familial dysautonomia

“…To validate these presumptions, we co-labeled for the transcription factor Six1, which is traditionally used as a marker of placode-derived neurons in the trigeminal ganglion ( Karpinski et al, 2016 ; Karpinski et al, 2022 ; Moody and LaMantia, 2015 ; Motahari et al, 2020 ). At E10.5, we observed that 88.6% of TrkA neurons, 78.0% of TrkB neurons, and 91.8% of TrkC neurons expressed Six1 ( Figure 6A, D, G and J ).…”

Lineage, Identity, and Fate of Distinct Progenitor Populations in the Embryonic Olfactory Epithelium

“…The temporal, regional and lineage-associated diversity of early OE precursors suggests that these cells differ in their proliferative characteristics. We used a pair cell assay (Shen et al, 2002; Tucker et al, 2010; Lehtinen et al, 2011; Karpinski et al, 2021) to distinguish modes of division and fates of isolated E11.5 medial versus lateral OE precursors. A Sox2 eGFP reporter expressed throughout the developing OE but not in the fnm (Ellis et al, 2004; Tucker et al, 2010) identifies presumed neural precursors from the dissected E11.5 medial and lateral OE ( Figure 5A ).…”

“…These distinctions may reflect local signals (see above) that impose positional identity on OE precursor subpopulations. Alternately, they may reflect local cell-cell interactions that nevertheless depend upon the influence of immediate neighbors of similar or distinct identities (Karpinski et al, 2021). Temporal specification of subsets of precursors may provide greater diversity of potential interactions.…”

Neural crest cell-placodal neuron interactions are mediated by Cadherin-7 and N-cadherin during early chick trigeminal ganglion assembly

“…Other pathways have been discovered to regulate cellular interactions occurring during initial chick trigeminal ganglion coalescence, including Slit1-Robo2, 11,16 Wnt, 39,40 Neuropilin/Semaphorin, 41,42 and various growth factors 43 (e.g., Platelet-Derived Growth Factor 44 ), with many of these also identified in the developing mouse trigeminal ganglion. 45,46 In chick embryos, Robo2 signaling likely modulates levels of N-cadherin post-translationally, but the mechanisms underlying this are still not well characterized. Upstream pathways regulating Cadherin-7 expression in neural crest cells also remain obscure, but it is plausible that the preceding signal transduction pathways could impact the expression of Cadherin-7 and/or N-cadherin during trigeminal gangliogenesis.…”