Scientists discover how a rare genetic disease disrupts key neural interactions in the developing brain

Every time you chew, talk, yawn, or feel the zap of a toothache, cranial nerve cells send electrochemical signals to your brain. Some of these neurons detect pain, while others detect facial muscle movements or skin sensations.

Now, in a new study published in Disease Models & Mechanisms, scientists at VTC’s Fralin Biomedical Research Institute, led by Anthony-Samuel LaMantia, describe the early development of pain- and motion-sensing neurons in the face and throat. The findings reveal a previously unexplored feature of brain and cranial nerve development underlying eating, swallowing and speech.

We were able to show for the first time that this momentary interaction between two groups of cells plays a crucial role in the regulation of movements and the innervation of pain in the face.”


Anthony-Samuel LaMantia, Professor and Director, Center for Neurobiology Research at the Fralin Biomedical Research Institute

Researchers examined early neural development in mouse embryos with DiGeorge syndrome, a rare genetic condition associated with neural and facial abnormalities. Like human patients born with DiGeorge, mice may carry the same genetic mutation, providing an ideal model to study where development goes wrong at the cellular and molecular level.

Children born with DiGeorge typically have trouble coordinating milk sucking and swallowing, a condition called pediatric dysphagia, but it’s unclear how the mutation causes these functional abnormalities. While the movements of the mouth, tongue, and throat involved in eating are controlled by motor neurons, mechanosensory neurons—a subject of this study—detect and integrate movement cues to fine-tune behavior. The study also assessed pain-sensing neurons, or nociceptors, that monitor potentially harmful aspects of eating behavior, including excessive temperatures and irritants like the capsaicin in hot peppers.

LaMantia and his lab have been studying this syndrome to unravel facets of cranial nerve development and oropharyngeal behaviors for a decade.

Based on their previous research, the scientists knew that on the ninth day of mouse embryo development, two groups of cells – the neural crest and the placode cells – had to meet to begin tracing the plane of the facial nerve. . They knew that in the syndromic mice, something was wrong at this stage of development that had deleterious behavioral consequences, but this required further investigation.

“Initially, we weren’t sure if these two cell groups weren’t migrating together to meet in the right place, or if they were in the right place at the right time, and just couldn’t communicate,” LaMantia said. . . With this newly released data, LaMantia’s lab now suspects the latter to be true.

By combining in vivo analysis and imaging to visualize a variety of molecular markers, the researchers discovered that neural crest cells were transforming into pain-sensing neurons far too soon. This premature differentiation increased the amount of placode cells, which become mechanosensory neurons, compared to neural crest cells.

This study builds on previous work from LaMantia’s lab. Seven years ago, researchers examined whether neurons in developing cranial nerves produced axons that responded to functional targets in the face, mouth and throat. They found that compared to regular mice, syndromic mouse embryos lacked proper innervation – axons were shorter, misplaced and disorganized.

“Not only were the neurons confused as to what they were supposed to do, but their axons also didn’t have precise destinations — they just got lost,” LaMantia said.

In a follow-up study, LaMantia’s lab identified key genes involved in regulating normal axon growth of the cranial nerve. Remarkably, the researchers were able to restore ordinary cranial nerve growth in mice with DiGeorge syndrome by deleting a specific gene.

The new finding reveals how changes in the expression of genes associated with DiGeorge syndrome destabilize the growth of sensory neurons by disrupting a key interaction between the neural crest and placode cells. LaMantia’s lab now aims to uncover the molecular signals these cell groups need to assemble a healthy cranial nerve.

“Now that we’ve identified the point of divergence where these functional oropharyngeal problems originate, our next step will be to understand the vocabulary these cells use to communicate with each other,” LaMantia said.

This research was funded in part by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, part of the National Institutes of Health; and the Fralin Biomedical Research Institute. LaMantia is also a professor in the Department of Biological Sciences at the College of Sciences and the Department of Pediatrics at Virginia Tech Carilion School of Medicine.

Source:

Journal reference:

Karpinski, BA, et al. (2022) Selective disruption of trigeminal sensory neurogenesis and differentiation in a mouse model of 22q11.2 deletion syndrome. Disease models and mechanisms. doi.org/10.1242/dmm.047357.

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