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Dis Model Mech ; 15(2)2022 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-33722956


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 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.

Birth Defects Res ; 112(16): 1194-1208, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32431076


BACKGROUND: Vitamin A regulates patterning of the pharyngeal arches, cranial nerves, and hindbrain that are essential for feeding and swallowing. In the LgDel mouse model of 22q11.2 deletion syndrome (22q11DS), morphogenesis of multiple structures involved in feeding and swallowing are dysmorphic. We asked whether changes in maternal dietary Vitamin A intake can modify cranial nerve, hindbrain and pharyngeal arch artery development in the embryo as well as lung pathology that can be a sign of aspiration dysphagia in LgDel pups. METHODS: Three defined amounts of vitamin A (4, 10, and 16 IU/g) were provided in the maternal diet. Cranial nerve, hindbrain and pharyngeal arch artery development was evaluated in embryos and inflammation in the lungs of pups to determine the impact of altering maternal diet on these phenotypes. RESULTS: Reduced maternal vitamin A intake improved whereas increased intake exacerbated lung inflammation in LgDel pups. These changes were accompanied by increased incidence and/or severity of pharyngeal arch artery and cranial nerve V (CN V) abnormalities in LgDel embryos as well as altered expression of Cyp26b1 in the hindbrain. CONCLUSIONS: Our studies demonstrate that variations in maternal vitamin A intake can influence the incidence and severity of phenotypes in a mouse model 22q11.2 deletion syndrome.

Front Neurol ; 11: 4, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32082240


Disrupted development of oropharyngeal structures as well as cranial nerve and brainstem circuits may lead to feeding and swallowing difficulties in children with 22q11. 2 deletion syndrome (22q11DS). We previously demonstrated aspiration-based dysphagia during early postnatal life in the LgDel mouse model of 22q11DS along with disrupted oropharyngeal morphogenesis and divergent differentiation and function of cranial motor and sensory nerves. We now ask whether feeding and swallowing deficits persist in adult LgDel mice using methods analogous to those used in human patients to evaluate feeding and swallowing dysfunction. Compared to wild-type mice, videofluoroscopic swallow study revealed that LgDel mice have altered feeding and swallowing behaviors, including slower lick rates, longer inter-lick intervals, and longer pharyngeal transit times with liquid consistency. Transoral endoscopic assessment identified minor structural anomalies of the palate and larynx in one-third of the LgDel mice examined. Video surveillance of feeding-related behaviors showed that LgDel mice eat and drink more frequently. Furthermore, LgDel animals engage in another oromotor behavior, grooming, more frequently, implying that divergent craniofacial and cranial nerve structure and function result in altered oromotor coordination. Finally, LgDel mice have significantly increased lung inflammation, a potential sign of aspiration-based dysphagia, consistent with results from our previous studies of early postnatal animals showing aspiration-related lung inflammation. Thus, oromotor dysfunction, feeding, and swallowing difficulties and their consequences persist in the LgDel 22q11DS mouse model. Apparently, postnatal growth and/or neural plasticity does not fully resolve deficits due to anomalous hindbrain, craniofacial, and cranial nerve development that prefigure perinatal dysphagia in 22q11DS. This new recognition of persistent challenges with feeding and swallowing may provide opportunities for improved therapeutic intervention for adolescents and adults with 22q11DS, as well as others with a history of perinatal feeding and swallowing disorders.