Overview
Dr. Ryan Gray is the Faculty Spotlight for this month. Dr. Gray is an Assistant Professor in the Department of Nutritional Sciences, with a courtesy appointment in the Department of Pediatrics in the Dell Medical School. He received his PhD in Cellular and Molecular Biology from UT-Austin, followed by a postdoctoral fellowship at Washington University School of Medicine, where he developed expertise in molecular genetics focused on a structural disorder of the spine called scoliosis. He continues this research in his own lab at the Dell Pediatrics Research Institute using both mouse and zebrafish animal models to model normal development and disorders of the spine.
Dr. Gray's interest in studying the spine was prompted by a mysterious genetic mutant uncovered by his postdoctoral mentor, modeling congenital scoliosis. While studying congenital scoliosis, Dr. Gray also began to learn about another more common form of spine disorder called adolescent idiopathic scoliosis. These children's spines develop normally up until they become adolescents and many go on to have very severe , debilitating spine curvatures or scoliosis, which may require surgical intervention. This abrupt shift, when development is normal but suddenly goes out of control, is referred to as a loss of homeostasis. Because the disorder is prevalent in children but the molecular genetics and cellular causes are not well-understood, Dr. Gray began to screen for the mutations that gave rise to scoliosis using the zebrafish models.
Currently, Dr. Gray's research carries out forward and reverse genetics using technologies such as CRISPR (clustered regularly interspaced short palindromic repeats) to edit or alter the sequence of certain genes using both zebrafish and mouse models.
What the Research has Shown so Far
A few years ago, one of the scoliosis zebrafish mutants that was uncovered by Dr. Gray's screens was shown to affect the SCO-spondin protein. The protein SCO-spondin is an essential component of the Reissner fiber, which is known to help maintain body straightness. When the scospondin mutants begin to get curvatures in the body, they lose the fiber due to a lack of excretion of the protein. The most exciting aspect of this discovery was that Dr. Gray and his lab were the first people to ever visualize the dynamic properties of the Reissner fiber in a living animal.
Dr. Gray and his team believe that motile cilia in the spinal canal play a role by generating fluid flow or possibly by contacting the Reissner fiber and pushing it along. Because they knew cilia were involved in the process of spine development, they utilized a dataset of motile cilia related genes, systemically knocking out these genes using CRISPR. This screening approach uncovered mutations in dnah10, which caused scoliosis in zebrafish. They went on to show that dnah10 mutant zebrafish displayed disrupted motile cilia movements and disassembly of the Reissner fiber. This failure of motile cilia motility generates the loss of fluid flow in the spinal cord. So what does this mean? This indicates a correlation between the speed and motility of cilia in the spinal canal with the disassembly of the Reissner fiber. All of the research conducted in zebrafish shows that aspects of the nervous system are extremely important for maintaining spine stability.
The Gray lab has also engineered novel mouse models of adolescent idiopathic scoliosis. Using conditional genetics studies, they have shown that the tissue specific loss of the adhesion G-protein coupled receptor G6 (Adgrg6) – one of the top hits in human adolescent idiopathic scoliosis worldwide – in the spine models this disorder in mice. This is the first mouse model of adolescent idiopathic scoliosis informed by human genetics studies. When the mice mutants get scoliosis, there is a reduced expression of transcription factor SOX9, and it appears as though Adgrg6 may be helping to control this expression. Finally, the Gray lab has shown that Adgrg6 is essential for the perinatal homeostasis of both cartilaginous elements for the intervertebral discs and dense connective tissues such as ligaments and tendon to help maintain typical spine alignment
Future Work
Dr. Gray hopes that what they are learning in animal models can inform the human etiology of adolescent idiopathic scoliosis moving forward. They are continuing to work with a noble collection of scoliosis mutant zebrafish, trying to figure out the genetic variants and underlying cell biology and pathologies that contribute to these scoliosis mutant phenotypes. They also have more defined molecular studies focused on Adgrg6 and SOX9 signaling in hopes to develop treatments for their preclinical animal models of adolescent idiopathic scoliosis and uncover whether other genes are synergistic with ADGRG6/SOX9 signaling.
Dr. Gray also wants to work with undergraduates and start an informal journal club to provide opportunities for students to get hands-on training in his lab!
Key Takeaway
Dr. Gray's lab is interested in using animal models to understand development in human musculoskeletal disorders, and they believe animal research is important in this process. Another takeaway he wants to share is, "Follow your passions and don't be afraid to fail. Get used to failing and love what you do!"