A new five-year, $2.5 million NIH/NIDCR R01 award is advancing research at the CU Anschutz School of Dental Medicine that aims to redefine how cell communication coordinates craniofacial development. Katherine Fantauzzo, PhD, Associate Professor and Vice Chair of the Department of Craniofacial, Oral and Materials Sciences, is leading a project focused on the platelet-derived growth factor receptors (PDGFRs), a family of cell surface receptors that initiate signaling relays within the cell. Activity of these receptors is essential to the formation of the human face.
“These receptors sit at the cell surface and allow the cells that will eventually become the bone and cartilage of the face to communicate with their environment,” Fantauzzo said.
Despite decades of study, key aspects of PDGFR signaling have remained unresolved—particularly how specific receptor pairings, or dimerization, drive distinct cellular outcomes. By developing and applying first-in-the-field tools to directly observe these dimerization dynamics in living systems, the Fantauzzo Laboratory is addressing that gap with a level of precision not previously possible.
A more precise view of a complex system
Craniofacial development depends on neural crest cells that migrate, proliferate and differentiate into the facial mesenchyme. PDGFR signaling helps coordinate these processes. When that signaling is disrupted, the result can be significant, including cleft lip and/or palate and syndromes characterized by craniofacial differences. The former affect nearly 1 in 1,000 births in the United States.
For decades, scientists have studied PDGFR activity, but with a critical limitation: the inability to distinguish between inactive receptors and the specific receptor pairs, known as dimers, that actually drive signaling.
Fantauzzo’s lab has addressed that gap directly. Using CRISPR-based genome engineering and a technique called bimolecular fluorescence complementation, the team created mouse models in which active PDGFR dimers emit a fluorescent signal. The approach allows researchers to visualize, isolate and analyze individual receptor dimers that are actively signaling.
“We developed new tools to tag these receptors so that when they dimerize, they emit a fluorescent signal, so now we can track their dynamics during craniofacial development,” Fantauzzo said.
The result is a set of first-in-the-field tools that remove longstanding ambiguity. Researchers can now track specific receptor dimers, measure when and where they form, and link those dynamics to changes in downstream signaling, gene expression and cell behavior.
Challenging a long-standing assumption
The implications extend beyond improved measurement. Early findings from the lab are reshaping a core assumption about how PDGFR signaling works.
Historically, scientists believed that once PDGFRs are activated at the cell surface and then internalized—pulled into the cell—the signaling process winds down. While a handful of studies have suggested otherwise, Fantauzzo’s work has significantly expanded on the connection between receptor internalization and downstream signaling.
Her team has shown that internalized receptors continue to signal, and that their movement through different compartments inside the cell plays a critical role in determining what that signal does.
“Internalization isn’t shutting the signal off—it’s shaping how the signal is propagated and how the cell ultimately responds,” Fantauzzo said.
Different dimer pairs follow distinct intracellular trafficking routes, leading to different outcomes. Routes that result in sustained signaling promote cell proliferation and migration—two behaviors that are central to how craniofacial structures form.
The NIH-funded project will systematically test this model, examining how ligand concentration affects receptor internalization, characterizing proteins that regulate trafficking and defining which intracellular compartments serve as key signaling platforms.
From mechanism to meaning
At its core, the research aims to connect molecular behavior to biological consequences.
“What we’re aiming to do is tie these different dynamics—how receptors are internalized and move throughout the cell—to cellular behavior during craniofacial development,” Fantauzzo said. “These processes are understudied in the field and may lead to novel insights.”
By linking specific receptor dynamics to specific outcomes, the work offers a more complete explanation for how disruptions in PDGFR signaling lead to craniofacial differences. It also opens new avenues for intervention.
Fantauzzo’s findings suggest that important aspects of signaling occur after internalization, raising the possibility of therapeutic strategies that precisely target these receptors within the cell.
Broader impact and shared resources
While the immediate focus is craniofacial development, the implications extend further. PDGFR signaling plays roles in cancer, vascular disease and fibrosis, making the underlying mechanisms broadly relevant.
The tools developed through this work are also designed to outlast the grant itself. Fantauzzo plans to deposit the engineered mouse models into national repositories, enabling researchers worldwide to apply them to studies in other tissues and organ systems.
“With these models, we can answer questions about these receptors in an unambiguous way and share those tools so others can do the same,” she said.
As the only lab currently applying this level of precision to PDGFR dimer dynamics in craniofacial development, the Fantauzzo Lab is not only advancing a specific line of inquiry—it is redefining how the field approaches receptor signaling altogether.
Explore the Department of Craniofacial, Oral and Materials Sciences at CU Anschutz Dental.
