Dysphagia and disrupted cranial nerve development in a mouse model of DiGeorge/22q11 Deletion Syndrome

Abstract

We assessed feeding-related developmental anomalies in the LgDel mouse model of chromosome 22q11 deletion syndrome (22q11DS), a common developmental disorder that frequently includes perinatal dysphagia – debilitating feeding, swallowing and nutrition difficulties from birth onward – within its phenotypic spectrum. LgDel pups gain significantly less weight during the first postnatal weeks, and have several signs of respiratory infections due to food aspiration. Most 22q11 genes are expressed in anlagen of craniofacial and brainstem regions critical for feeding and swallowing, and diminished expression in LgDel embryos apparently compromises development of these regions. Palate and jaw anomalies indicate divergent oro-facial morphogenesis. Altered expression and patterning of hindbrain transcriptional regulators, especially those related to retinoic acid (RA) signaling, prefigures these disruptions. Subsequently, gene expression, axon growth and sensory ganglion formation in the trigeminal (V), glossopharyngeal (IX) or vagus (X) cranial nerves (CNs) that innervate targets essential for feeding, swallowing and digestion are disrupted. Posterior CN IX and X ganglia anomalies primarily reflect diminished dosage of the 22q11DS candidate gene Tbx1. Genetic modification of RA signaling in LgDel embryos rescues the anterior CN V phenotype and returns expression levels or pattern of RA-sensitive genes to those in wild-type embryos. Thus, diminished 22q11 gene dosage, including but not limited to Tbx1, disrupts oro-facial and CN development by modifying RA-modulated anterior-posterior hindbrain differentiation. These disruptions likely contribute to dysphagia in infants and young children with 22q11DS.

Disruption of CXCR4 signaling in pharyngeal neural crest cells causes DiGeorge syndrome-like malformations

“…Taken together, our results demonstrate that disrupting CXCR4 signals in pharyngeal NCs induces a large spectrum of abnormalities in their skeletal, neuronal and glandular derivatives, which, in addition to the cardiac defects already reported (Escot et al, 2013), recapitulate the defects described in mouse models and DGS patients (Funato et al, 2015;Karpinski et al, 2014;Vitelli et al, 2002).…”

“…Finally, disrupted cranial nerves have been reported in the LgDel mouse, possibly accounting for the dysphagia observed in children diagnosed with DGS (Karpinski et al, 2014). Pharyngeal NCs contribute to some of the major cranial sensory ganglia, i.e.…”

“…S5) or a dominant-negative form of Cxcr4 (DN-CXCR4) lacking the C-terminus sequences necessary for chemotactic migration (Ahr et al, 2005;Cronshaw et al, 2010). First, we searched for craniofacial dysmorphogenesis due to palate and jaw anomalies, a prominent trait of DGS patients (Fukui et al, 2000;Karpinski et al, 2014). Heads of chick embryos were collected at E9.5 and the jaw anatomy examined.…”

22q11.2 deletion syndrome

“…Pharyngeal mesoderm progenitor cells give rise to craniofacial muscles and second heart field derivatives, including the cardiac outflow tract 64,78 . The facial bones and bony palate are variously derived from neural crest cells or the anterior mesoderm.…”

Делеція 22q11.2 хромосоми: світові критерії визначення, стандарти діагностики та моніторингу

“…Краніофасціальні м'язи, серце, аорта та легенева артерія -з глоткової мезодерми; кістки обличчя та твердого піднебіння -з клітин нервового гребеня та передньої мезодерми. Паращитоподібна залоза й тимус виникають унаслідок взаємодії тканин між ендодермою глотки та клітинами нервового гребеня [8,9].…”