22q11Deletion Syndrome (22q11DS) patients have feeding and swallowing difficulties that compromise their nutritional status and increase nasal, middle ear, and respiratory infections due to aspiration and reflux. The causes of these clinically significant difficulties are unknown. Using the genetically accurate LgDel mouse model of 22q11DS, which has similar phenotypic features, we found that retinoic acid-mediated anterior- posterior patterning of the hindbrain is altered, and that several of the cranial nerves that control feeding and swallowing have aberrant growth patterns early in development. These observations suggest that aberrant development of the hindbrain motor and/or sensory neurons leads to dysfunction of the network of cranial neurons that are needed to execute feeding and swallowing. We will test the hypothesis that diminished 22q11 gene dosage disrupts anterior-posterior (A-P) hindbrain patterning via retinoic acid (RA) signaling, and thereby re-specifies brainstem and/or neural crest precursor cells, leading to dysphagia. Our experiments in Specific Aim 1 will quantify RA production to assess excess ligand availability, measure hindbrain RA responses to evaluate enhanced RA sensitivity, and determine changes of additional patterning centers and their targets in LgDel embryos where anterior CNs are compromised, Tbx1+/- where they are spared, and LgDel:Raldh2+/- where they are rescued. To identify genes that, if mutated, predispose at-risk fetuses to dysphagia, in Specific Aim 2 we will compare transcriptomes from the hindbrains of WT embryos, LgDel embryos in which RA signaling is enhanced, and LgDel:Raldh2+/- embryos in which it is returned to WT levels. Finally, in Specific Aim 3 we will characterize position, molecular identity, frequency, proliferative, and/or migratory capacities of anterior versus posterior hindbrain motor neuron, interneuron, pre-migratory and migratory neural crest precursors in LgDel embryos in which anterior CNs are compromised, Tbx1+/- in which they are spared, and LgDel:Raldh2+/- in which they are rescued. The results of PROJECT 2 will establish the developmental origins of pediatric dysphagia pathology defined by PROJECT 1, and determine how these mechanisms contribute to specific aspects of disrupted feeding and swallowing. Our data will define new molecular pathways for fetal and early postnatal diagnosis, and targeted therapeutic interventions. Experiments in PROJECT 3 will evaluate the precision of these targets for correcting key aspects of dysphagia pathology in fetuses at risk for perinatal feeding and swallowing difficulties.

Public Health Relevance

Patients with 22q11 Deletion Syndrome have neurodevelopmental disabilities complicated by feeding and swallowing difficulties associated with increased nasal, middle ear and respiratory infections. The causes are unknown, but likely reflect altered early development. To identify the developmental origins of dysphagia pathology, this project will determine the changes in differentiation in parts of the brain that control feeding and swallowing in embryos of genetically accurate mouse models of 22q11DS.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Program Projects (P01)
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Pediatrics Subcommittee (CHHD-A)
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George Washington University
Domestic Higher Education
United States
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Wang, Xin; Bryan, Corey; LaMantia, Anthony-Samuel et al. (2017) Altered neurobiological function of brainstem hypoglossal neurons in DiGeorge/22q11.2 Deletion Syndrome. Neuroscience 359:1-7
Karpinski, Beverly A; Bryan, Corey A; Paronett, Elizabeth M et al. (2016) A cellular and molecular mosaic establishes growth and differentiation states for cranial sensory neurons. Dev Biol 415:228-241
LaMantia, Anthony-Samuel; Moody, Sally A; Maynard, Thomas M et al. (2016) Hard to swallow: Developmental biological insights into pediatric dysphagia. Dev Biol 409:329-42
Baker, Jennifer L; Wood, Bernard; Karpinski, Beverly A et al. (2016) Testicular receptor 2, Nr2c1, is associated with stem cells in the developing olfactory epithelium and other cranial sensory and skeletal structures. Gene Expr Patterns 20:71-9
Meechan, Daniel W; Maynard, Thomas M; Tucker, Eric S et al. (2015) Modeling a model: Mouse genetics, 22q11.2 Deletion Syndrome, and disorders of cortical circuit development. Prog Neurobiol 130:1-28
Paronett, Elizabeth M; Meechan, Daniel W; Karpinski, Beverly A et al. (2015) Ranbp1, Deleted in DiGeorge/22q11.2 Deletion Syndrome, is a Microcephaly Gene That Selectively Disrupts Layer 2/3 Cortical Projection Neuron Generation. Cereb Cortex 25:3977-93