Highlights d Cortical connections decrease in a DiGeorge/22q11 deletion syndrome mouse model d Under-connectivity reflects reduced dendrite, axon, and synapse growth d Txrnd2, a 22q11 gene, regulates mitochondrial metabolism and neuron growth d Cortical connections and behavioral deficits are restored by anti-oxidant therapy
We compared apparent origins, cellular diversity and regulation of initial axon growth for differentiating cranial sensory neurons. We assessed the molecular and cellular composition of the developing olfactory and otic placodes, and cranial sensory ganglia to evaluate contributions of ectodermal placode versus neural crest at each site. Special sensory neuron populations—the olfactory and otic placodes—as well as those in vestibulo-acoustic ganglion are entirely populated with cells expressing cranial placode-associated, rather than neural crest-associated markers. The remaining cranial sensory ganglia are a mosaic of cells that express placode-associated as well as neural crest-associated markers. We found two distinct populations of neural crest in the cranial ganglia: the first, as expected, is labeled by Wnt1:Cre mediated recombination. The second is not labeled by Wnt1:Cre recombination, and expresses both Sox10 and FoxD3. These populations—Wnt1:Cre recombined, and Sox10/Foxd3-expressing— are proliferatively distinct from one another. Together, the two neural crest-associated populations are substantially more proliferative than their placode-associated counterparts. Nevertheless, the apparently placodal and crest-associated populations are similarly sensitive to altered signaling that compromises cranial morphogenesis and differentiation. Acute disruption of either Fibroblast growth factor (Fgf) or Retinoic acid (RA) signaling alters axon growth and cell death, but does not preferentially target any of the three distinct populations. Apparently, mosaic derivation and diversity of precursors and early differentiating neurons, modulated uniformly by local signals, supports early cranial sensory neuron differentiation and growth.
DiGeorge/22q11.2 Deletion Syndrome (22q11DS) is a common genetic microdeletion syndrome that underlies several neurodevelopmental disorders including autism, attention deficit/hyperactivity disorder, and schizophrenia. In addition to cognitive impairments, those with 22q11DS have disrupted feeding and swallowing from birth onward. This perinatal dysphagia significantly compromises nutritional status, impairs appropriate weight gain, and can lead to life threatening aspiration-based infections. Appropriately timed excitation and inhibition of brainstem hypoglossal motor neurons, which innervate tongue muscles, is essential for proper feeding and swallowing. In this study we have examined changes in hypoglossal motor neuron function in the LgDel mouse model of 22q11DS. Hypoglossal motor neurons from LgDel mouse pups have action potentials with afterhyperpolarizations, mediated by a large conductance charybdotoxin-sensitive Ca activated K current, that are significantly shorter in duration and greater in magnitude than those in wild type pups. In addition, the amplitude, but not frequency, of glutamatergic EPSCs is diminished, and GABAergic, but not glycinergic, neurotransmission to hypoglossal motor neurons was reduced in LgDel animals. These observations provide a foundation for understanding the neurological changes in hypoglossal motor neuron function and their contribution to swallowing abnormalities that occur in DiGeorge/22q11.2 Deletion Syndrome.
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 asked 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. As the ganglion coalesces, however, 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 E9.5, and premature neurogenesis from neural crest-derived precursors, reflected by 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 P8, 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.
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