Evolutionary and developmental geneticist Craig Albertson, biology, has received a five-year, $1.76 million National Institutes of Health grant to study the development of the craniofacial skeleton, work he says will address a significant knowledge gap. Albertson explains, “While we know a lot about how the skull and facial skeleton form, we know comparatively very little about how the head is shaped over development.”
Albertson’s lab will first use a combination of micro-CT scanning, 3D reconstructions and genetic mapping in cichlid fish to generate hypotheses about the specific genes that control head shape variation. Cichlids are famous for their remarkable morphological diversity, including craniofacial diversity, and are therefore an excellent model for such studies, he says. Next, he and colleagues will test these genetic hypotheses by manipulating the genomes of zebrafish, what he calls “a powerful experimental model system,” to look for differences in skull shape.
For related work, Albertson and co-principal investigator Rolf Karlstrom, biology,also received a three-year, $747,000 National Science Foundation grant to investigate the molecular cues that allow bone to sense and respond to its mechanical environment. Albertson says, “It’s long been known that bone is a dynamic tissue that can respond to all sort of environmental cues including nutrition, hormones, exercise or mechanical use, but the cellular and molecular mechanisms that enable this ability are not well known. We have some nice assays set up where we can make fish chew on hard or soft food. We’ve shown that just that mechanical influence over a couple of months is sufficient to change the shape and density of bone in predictable ways.”
In addition, he and colleagues have shown that increasing or decreasing Hedgehog molecular signaling pathway activity affects bone deposition. “With this grant we will try to understand how the two fit together,” Albertson says. “Our hypothesis is that bone cells are sensing their mechanical environment using an organelle called the primary cilium, and that biophysical force on this organelle is transducing a signal into the cell using the Hedgehog molecular machinery.” The Hedgehog signaling pathway transmits information required for proper cell differentiation to the embryo. The name is said to come from the spiky look of mutant fruit fly larvae in which the pathway was discovered.
The evolutionary and developmental geneticist says of both studies, “We’re not just talking about fish bones here. We’re talking about the big picture of how the skeleton is shaped over both developmental and evolutionary time. The implications of this work are far-reaching. The head is one of the most evolvable features of vertebrate. You can tell a lot about where an animal lives, and how it makes a living, just by looking at its head.”
One of the “big picture” impacts of this new knowledge may be in forensics, Albertson says. “Technology has advanced to the point where we can obtain vast amounts of genetic information from just a speck of tissue. It is fun to speculate that with knowledge of the genetic variants that regulate the dimensionality of the skull, we may ultimately be able to reconstruct the facial features of long-dead animals. Maybe someday we’ll be able to reconstruct a face to know exactly what Richard III looked like, or even an ancient human ancestor like the denisovans, known only from bone fragments. It’s an exciting prospect.”
Further, the craniofacial skeleton is one of the most frequently affected by human birth defects and malformations such as cleft palate, the biologist notes. Albertson says, “A major challenge for biologists is to reveal the full spectrum of genes and genetic interactions that contribute to normal and clinical variation in craniofacial shape.”
These studies will use a number of lines of transgenic zebrafish developed by Karlstrom in which the researchers are able to manipulate the Hedgehog signaling pathway in a time-specific manner. They will also use CRISPR/Cas9-mediated genome editing to generate zebrafish lines with defective cilia.
The work will shed light on how biodiversity arises and is maintained, Albertson says. All vertebrate species have the ability to modify their skeletons in response to local environmental shifts such as new foods or new predators. Such abilities can “lead to measurable adaptive changes within a generation, as well as expose new patterns of phenotypic variation to natural selection,” Albertson explains. “In the later case, the environment has the potential to significantly influence the path of evolution. We want to dissect the interplay between molecules, cells and the environment. We know the environment is changing pretty rapidly in some places, which makes this pretty relevant in nature today.”