By Jack Lee | August 17, 2022
About one-third of human birth defects affect the head and face. Cleft palate, for example, happens when the tissue on the roof of a baby’s mouth does not join together completely during pregnancy.
Soma Dash is investigating the molecular pathways underlying craniofacial anomalies. She is a developmental and molecular biologist in the Trainor Lab at the Stowers Institute.
“While treatment through multiple surgeries is possible for some of the syndromes, treatment options are not readily available everywhere and are expensive,” Dash said. “By studying craniofacial development in detail, we hope to identify novel genes and pathways that can provide new therapeutic avenues.”
Dash recently received a National Institutes of Health Pathway to Independence Award. The K99/R00 program helps outstanding postdoctoral researchers transition to independent research careers. It supports an initial mentored phase, followed by an independent phase.
The formation of the face during embryogenesis is a complex process. It involves the coordinated activity of multiple types of cells, including the neural crest cells. These cells only appear only during development.
“The neural crest cell population is a transient migratory cell population,” Dash said. “It originates only during mid-gestation, at the border of the neuroectoderm.”
Neural crest cells migrate throughout the embryo and differentiate upon reaching their final destinations. They give rise to a variety of tissues, including craniofacial cartilage, bone, and connective tissue. They also contribute to the peripheral nervous system.
Cranial placodes are another important cell population. These cells produce sensory organs in the head. “There are six cranial placodes, of which the olfactory that enables the sensory feature of our nose. The lens placode that generates part of the eye. Theotic placode gives rise to the inner ear,” Dash said.
In 2011, the Trainor Lab described a genetic screen that identified new mutant mice with craniofacial developmental defects. One of the mutants, dubbed snouty, had multiple defects, including a shortened snout and blood vessel anomalies.
Dash and colleagues determined that snouty mice have a mutation in Med23. This gene encodes a subunit of the Mediator complex, a multi-protein assembly required for transcription, the process of making RNA from DNA. Recent findings indicate that Mediator is an important coordinator of development and cell fate determination.
The researchers discovered that mice with mutated Med23 had elevated signaling through the Wnt pathway. Wnt signaling regulates many processes during development. The pathway also plays important roles in tissue homeostasis and disease.
The team discovered that perturbed Wnt signaling in snouty mutant mice prevented cranial placodes from developing properly. This failure led to abnormal development of the cranial sensory nervous system.
This tissue-specific role for a Med23 was a surprise. “Mediator is required in every cell type of our body,” Dash said. “But deleting one of its subunits affects tissues specifically during early development. That was very exciting”
Med23 in Neural Crest Cells
Dash and colleagues recently uncovered another role for Med23 during craniofacial development, in neural crest cells. When the team specifically knocked out Med23 from neural crest cells in mice, the embryos had defects resembling Pierre Robin sequence in humans.
“There’s a trifecta of defects occurring in this sequence,” Dash said. “The lower jaw is small. That displaces the tongue. The tongue forms over the roof of the mouth and that blocks the airways.”
The team found that Med23 binds to the promoter region of the Sox9 gene, which is a master regulator of cartilage differentiation and represses its expression in vitro. They propose that, in the absence of Med23, increased levels of Sox9 result in downregulation of genes involved in cartilage formation and cell proliferation. This altered expression leads to altered jaw formation and cleft palate.
Dash is continuing to investigate the role that Med23 plays in craniofacial development, such as the proteins and DNA sequences that Med23 binds to. She is also exploring the blood vessel defects in Med23 mutant mice.
“What I’m trying to do now is understand how neural crest cells and vasculature develop codependently during development, to make a proper head,” Dash said. She is also studying how ribosome biogenesis, a process required for protein synthesis in all cells, plays a role in specific developmental processes. Together, her research may lead to new treatment options for craniofacial anomalies.