Transcriptional dysregulation in developing trigeminal sensory neurons in the LgDel mouse model of DiGeorge 22q11.2 deletion syndrome

Abstract

LgDel mice, which model the heterozygous deletion of genes at human chromosome 22q11.2 associated with DiGeorge/22q11.2 deletion syndrome (22q11DS), have cranial nerve and craniofacial dysfunction as well as disrupted suckling, feeding and swallowing, similar to key 22q11DS phenotypes. Divergent trigeminal nerve (CN V) differentiation and altered trigeminal ganglion (CNgV) cellular composition prefigure these disruptions in LgDel embryos. We therefore asked whether a distinct transcriptional state in a specific population of early differentiating LgDel cranial sensory neurons, those in CNgV, a major source of innervation for appropriate oropharyngeal function, underlies this departure from typical development. LgDel versus wild-type (WT) CNgV transcriptomes differ significantly at E10.5 just after the ganglion has coalesced. Some changes parallel altered proportions of cranial placode versus cranial neural crest-derived CNgV cells. Others are consistent with a shift in anterior–posterior patterning associated with divergent LgDel cranial nerve differentiation. The most robust quantitative distinction, however, is statistically verifiable increased variability of expression levels for most of the over 17 000 genes expressed in common in LgDel versus WT CNgV. Thus, quantitative expression changes of functionally relevant genes and increased stochastic variation across the entire CNgV transcriptome at the onset of CN V differentiation prefigure subsequent disruption of cranial nerve differentiation and oropharyngeal function in LgDel mice.

Why Does the Face Predict the Brain? Neural Crest Induction, Craniofacial Morphogenesis, and Neural Circuit Development

“…We have begun to assess interactions between neural crest and placodal cells underlying development of cranial somatosensory ganglia. The dual origin of cranial ganglion sensory neurons, as well as their divergent fates -primarily mechanoreceptive for placode descendants, nociceptive for those from the neural crest (D' Amico- Martel and Noden, 1983) -is well established, and our analyses in the mouse (Karpinski et al, 2016;Maynard et al, 2020a;Motahari et al, 2020) confirmed and extended earlier studies. Using transcriptional lineage tracing, we identified diversity within the neural crest population (Figure 4).…”

“…Instead, 22q11DS phenotypes may result from altered neural crest-mediated interactions with mesodermal or endodermal targets that express Tbx1. Our evidence suggest that a significant portion of the 22q11DS phenotypic spectrum reflects the coordinated expression of multiple 22q11 genes and their dosagesensitive influence on neural crest-mediated M/E induction beyond that of Tbx1 (Maynard et al, 2013(Maynard et al, , 2020aKarpinski et al, 2014;Motahari et al, 2020). These 22q11 genes have reciprocal regulatory interactions with cardinal inductive signaling pathways critical for optimal M/E induction at each of the phenotypic sites.…”

“…22q11DS is a global developmental disorder whose phenotypic spectrum includes highly penetrant cardiovascular malformations, as well as craniofacial anomalies, mild limb and digit anomalies, and a high frequency of behavioral difficulties that resemble clinically diagnosed neurodevelopmental disorders, including schizophrenia, autistic spectrum disorder, and attention deficit disorder, accompanied by altered brain morphology and function (Schneider et al, 2014;McDonald-McGinn et al, 2015;Rogdaki et al, 2020). 22q11DS, as the name suggests, is not caused by a single loss-of-function mutation but deletion of a limited number of genes: minimally 32 in humans (Morrow et al, 2018) and their subsequent approximately 50% diminished expression (Meechan et al, 2006;Maynard et al, 2008Maynard et al, , 2013Maynard et al, , 2020a). There is a high level of conservation of these genes, as a colinear set, across multiple vertebrates, including the mouse, in which 28 of the 32 minimally critically deleted genes are found adjacent to one another on murine Chromosome 16 (Meechan et al, 2015).…”

Aberrant early growth of individual trigeminal sensory and motor axons in a series of mouse genetic models of 22q11.2 deletion syndrome

“…These phenotypes, like several others associated with heterozygous deletion of 22q11.2 genes (reviewed by 1 , 54 ), are subtle and variable. This partial penetrance may reflect stochastic variation in gene expression associated with aneuploidy ( 55 , 56 ), including in the LgDel +/− CNgV ( 7 ). Thus, at each critical step of CN V morphogenesis and differentiation: hindbrain and cranial placode patterning, neurogenesis or migration and early axon growth, 22q11.2 deletion in any individual embryo may yield variable cell-by-cell gene expression levels—ranging from 2 to 1 N to null—and similarly variable phenotypes.…”

“…Accordingly, we asked whether disrupted RA-related patterning critically influences CN V axon growth in the context of 22q11.2 deletion. In addition, we recently reported statistically significant stochastic variation in gene expression levels across the entire LgDel +/− CNgV transcriptome ( 7 ). Thus, the penetrance of individual 22q11.2 gene-related CN V axon phenotypes, at least for sensory neurons, might vary substantially, perhaps due to cell-by-cell transcriptional variation.…”