Abstract
BackgroundVitamin 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.MethodsThree 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.ResultsReduced 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.ConclusionsOur 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.
Highlights
Vitamin A regulates patterning of the pharyngeal arches, cranial nerves, and hindbrain that are essential for feeding and swallowing
To determine if altering the vitamin A content of the maternal diet has similar effects, we evaluated the impact on formation of the pharyngeal arch arteries (PAAs) in LgDel embryos and wild type (WT) littermates from WT dams fed 4, 10, and 16 IU vitamin A per gram diets mated to LgDel males
Our focus on vitamin A as a modifier for pediatric dysphagia in this study was prompted by previous studies demonstrating interactions between altered retinoic acid (RA) signaling and the incidence and severity of phenotypes in mouse models of 22q11DS
Summary
22q11.2 deletion syndrome (22q11DS) is the most frequent deletion syndrome in humans affecting an estimated one in 4,000 live births (Papangeli & Scambler, 2013). One-third of 22q11DS patients are unable to obtain sufficient nutrients by mouth and require enteral feeding to maintain adequate caloric intake (Eicher et al, 2000). Dysphagia in LgDel neonates is prefigured by irregularities in the appearance of cranial nerves at embryonic Day 10.5 (E10.5), altered hindbrain gene expression, as well as malformations of structures required for normal feeding such as the palate (Karpinski et al, 2014; LaMantia et al, 2016). Our results indicate changes in maternal vitamin A intake modifies the incidence and severity of abnormalities in cranial nerve branching and PAA formation, alters gene expression in the hindbrain and increases lung inflammation in the LgDel model of 22q11DS
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