Disrupted Coordination of Hypoglossal Motor Control in a Mouse Model of Pediatric Dysphagia in DiGeorge/22q11.2 Deletion Syndrome

Wang, Xin; Popratiloff, Anastas; Motahari, Zahra; LaMantia, Anthony S.; Mendelowitz, David

doi:10.1523/eneuro.0520-19.2020

Cited by 4 publications

(4 citation statements)

References 37 publications

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“…The sizes, gene expression profiles, and differentiation of subsets of cranial sensory and motor neurons are disrupted in LgDel pups (Karpinski et al, 2014;Wang et al, 2020). Finally, altered hypoglossal motor neuron activity, including divergent dysregulation of protruder and retractor tongue muscles, is seen in LgDel pups (Wang et al, 2017(Wang et al, , 2020, prefiguring craniofacial anomalies as well as disruption of tongue movement and feeding-related behaviors seen in adult LgDel mice (Welby et al, 2020).…”

Section: Swallow Hard: Does the Face Predict The Brain And Behavior Fmentioning

confidence: 99%

“…Cranial motor neurons essential for S/F/S are also compromised in LgDel pups. Intrinsic excitable properties, firing rates, and effectiveness of excitatory vs. inhibitory inputs onto hypoglossal and laryngeal motor neurons are compromised in LgDel pups (Wang et al, 2017(Wang et al, , 2020. These changes differ for hypoglossal motor neurons that project to protruder vs. retractor muscles of the tongue, and there are selective changes in dendritic architecture for these two target muscle-defined neuron classes (Wang et al, 2020).…”

Section: Swallow Hard: Does the Face Predict The Brain And Behavior Fmentioning

confidence: 99%

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

LaMantia

2020

Front. Physiol.

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Mesenchephalic and rhombencephalic neural crest cells generate the craniofacial skeleton, special sensory organs, and subsets of cranial sensory receptor neurons. They do so while preserving the anterior-posterior (A-P) identity of their neural tube origins. This organizational principle is paralleled by central nervous system circuits that receive and process information from facial structures whose A-P identity is in register with that in the brain. Prior to morphogenesis of the face and its circuits, however, neural crest cells act as “inductive ambassadors” from distinct regions of the neural tube to induce differentiation of target craniofacial domains and establish an initial interface between the brain and face. At every site of bilateral, non-axial secondary induction, neural crest constitutes all or some of the mesenchymal compartment for non-axial mesenchymal/epithelial (M/E) interactions. Thus, for epithelial domains in the craniofacial primordia, aortic arches, limbs, the spinal cord, and the forebrain (Fb), neural crest-derived mesenchymal cells establish local sources of inductive signaling molecules that drive morphogenesis and cellular differentiation. This common mechanism for building brains, faces, limbs, and hearts, A-P axis specified, neural crest-mediated M/E induction, coordinates differentiation of distal structures, peripheral neurons that provide their sensory or autonomic innervation in some cases, and central neural circuits that regulate their behavioral functions. The essential role of this neural crest-mediated mechanism identifies it as a prime target for pathogenesis in a broad range of neurodevelopmental disorders. Thus, the face and the brain “predict” one another, and this mutual developmental relationship provides a key target for disruption by developmental pathology.

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Section: Swallow Hard: Does the Face Predict The Brain And Behavior Fmentioning

confidence: 99%

Section: Swallow Hard: Does the Face Predict The Brain And Behavior Fmentioning

confidence: 99%

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

LaMantia

2020

Front. Physiol.

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“…XII innervates the tongue muscles, consisting of tongue protruders and tongue retractors. Ventral XII contains motoneurons for the protruders, while retractors originate in the dorsal XII ( Fig 3E ) (Wang et al, 2020). MOR and DOR scatter sparsely among XII motoneurons ( Fig 3E ).…”

Section: Resultsmentioning

confidence: 99%

Opioid receptor architecture for the modulation of brainstem functions

Hug

Lindsay

McCallum

et al. 2022

Preprint

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Opioids produce profound and diverse effects on a range of behaviors, many driven by brainstem activity; however, the presence of opioid and opioid-like receptors at this level has been poorly studied outside of nociceptive structures and components of respiratory circuitry. While previous studies identified expression of these receptors in the brainstem, patterns have not been fully delineated and neither has coexpression of receptors nor the behavioral implications of their expression in most structures. We aimed to elucidate expression of all four receptors across somatosensory-motor, auditory, and respiratory brainstem circuits; identify recurring themes to provide insight into the mechanisms by which exogenous opioids affect broader brainstem circuits; and characterize the function of endogenous opioids in subcortical processing and behavior modulation. Using a fluorescent reporter mouse line for each receptor, we created a three-dimensional, comprehensive atlas of brainstem receptor distribution and identified novel expression patterns in modality-specific circuits. Each receptor showed unique expression patterns across the brainstem with minimal correlation between receptors. Orofacial somatosensory-motor circuits expressed all four receptors, though generally in distinct nuclei, suggesting differential opiate modulation of afferent and efferent trigeminal signaling. Within the auditory circuit, receptors segregated along the vertical and horizontal processing pathways with minimal colocalization. Finally, the respiratory circuit strongly expressed the μ opioid receptor in multiple crucial structures with minimal presence of the other three receptors. We further assessed the functional significance of this expression pattern in the respiratory circuitry by characterization respiratory responses to selective opioid agonists, finding that each agonist caused unique alterations in breathing pattern and/or breath shape. Together, the results establish a comprehensive atlas of opioid and opioid-like receptor expression throughout the brainstem, laying the essential groundwork for further evaluation of opioid neuromodulation across the spectrum of behaviors.

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“…It is not yet clear whether the suckling, feeding and swallowing impairments that accompany 22q11 deletion are primarily due to structural dysmorphology, or are instead a consequence of aberrant neural development, such as the disrupted cranial sensory innervation ( 16 , 54 ) and aberrant brainstem motor neuron function ( 55 ) observed in the LgDel mouse. Ranbp1 −/− mutants do have hindbrain patterning disruptions and cranial nerve dysmorphology that are similar to, but more severe than those seen in LgDel ( 16 , 19 ); however, neither consistent hindbrain patterning changes nor statistically significant cranial nerve disruptions are seen in Ranbp1 +/− embryos.…”

Section: Discussionmentioning

confidence: 99%

Ranbp1modulates morphogenesis of the craniofacial midline in mouse models of 22q11.2 deletion syndrome

Paronett

Bryan

Maynard

et al. 2023

Human Molecular Genetics

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Facial dysmorphology is a hallmark of 22q11.2 Deletion Syndrome (22q11DS). Nearly all affected individuals have facial features characteristic of the syndrome: a vertically-long face with broad nasal bridge, narrow palpebral fissures and mild micrognathia, sometimes accompanied by facial skeletal and oropharyngeal anomalies. Despite the frequency of craniofacial dysmorphology due to 22q11.2 deletion, there is still incomplete understanding of the contribution of individual 22q11 genes to craniofacial and oropharyngeal development. We asked whether homozygous or heterozygous loss of function of single 22q11 genes compromises craniofacial and/or oropharyngeal morphogenesis related to these 22q11DS phenotypes. We found that Ranbp1, a 22q11DS gene that mediates nucleocytoplasmic protein trafficking, is a dosage-dependent modulator of craniofacial development. Ranbp1−/− embryos have variably penetrant facial phenotypes, including altered facial morphology and cleft palate. This 22q11DS-related dysmorphology is particularly evident in the midline of the facial skeleton, as evidenced by a robustly quantifiable dysmorphology of the vomer, an unpaired facial midline bone. 22q11DS-related oropharyngeal phenotypes reflect Ranbp1 function in both the cranial neural crest and cranial ectoderm based upon tissue-selective Ranbp1 deletion. Analyses of genetic interaction show that Ranbp1 mutation disrupts BMP signaling-dependent midline gene expression and BMP-mediated craniofacial and cranial skeletal morphogenesis. Finally, midline defects that parallel those in Ranbp1 mutant mice are observed at similar frequencies in the LgDel 22q112DS mouse model. Apparently, Ranbp1 is a modulator of craniofacial development, and in the context of broader 22q11 deletion, Ranbp1 mutant phenotypes mirror key aspects of 22q11DS midline facial anomalies.

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Disrupted Coordination of Hypoglossal Motor Control in a Mouse Model of Pediatric Dysphagia in DiGeorge/22q11.2 Deletion Syndrome

Cited by 4 publications

References 37 publications

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

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

Opioid receptor architecture for the modulation of brainstem functions

Ranbp1modulates morphogenesis of the craniofacial midline in mouse models of 22q11.2 deletion syndrome

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