Ali Berry
Research Mentor(s): Yuji Mishina
Department or Program: BMSP
Authors: Ali Berry, Hiroki Ueharu, Yuji Mishina
Session: Session 2: 1:00pm-1:50pm
Poster: 5
Abstract
Craniosynostosis is a developmental disorder characterized by the premature fusion of cranial sutures during embryonic and postnatal stages. Affecting roughly one in every 2000 births in the US, the current treatment for this condition is calvarial vault remodeling, in which the surgeon will perform an incision in the infant’s skull to manually unlock and reshape the prematurely fused suture. In complex cases, several surgeries are required during the child’s development to maintain the patency of the suture. These sutures are composed of Cranial Neural Crest Cells (CNCCs), which develop and maintain the craniofacial mesenchyme while differentiating into osteoblasts to form bones at appropriate timing. However, it is known that the posterior frontal (PF) suture closes along with cartilage formation during the PF suture development, uniquely displaying endochondral ossification. The presence of cartilage in the craniofacial sutures is specific to endochondral ossification, typically displayed in long bones. Through utilizing transgenic animals, we and other labs have demonstrated that the presence of ectopic cartilage in sutures causes premature fusion. As a recent report showed, this ectopic cartilage is present in human tissue specimens suffering from craniosynostosis, allowing us to speculate that the premature suture closure through endochondral ossification may be one of the causative mechanisms for craniosynostosis. While the developmental mechanisms of ectopic cartilage are not yet certain, it has been reported that the expansion of DDR2-expressing cell populations in sutures is critical to develop cartilage in sutures. Our transgenic mice expressing constitutively activated BMP type 1 receptor (caBmpr1a) in NCCs (P0-Cre;caBmpr1a mice) develop ectopic cartilage containing DDR2+ cells. We also found excess cell death in P0-Cre;caBmpr1a mice. However, it is still unclear how those two mechanisms cooperatively develop ectopic cartilage. In most cases, cranial sutures are formed via intramembranous ossification, in which mesenchymal cells differentiate directly into osteoblasts to form bone. In this study, we seek to understand how the unique development of the Posterior Frontal (PF) suture through endochondral ossification, where mesenchymal cells differentiate into chondrocytes first then into osteoblasts, could explain the pathological mechanisms for craniosynostosis. We hypothesize that BMP signaling contributes to developing the PF suture by the expansion of DDR2+ cell population through excess cell death in other cell types, and we aim to determine if BMP-induced cell death in other cell types prompts the expansion of DDR2+ cells. Through utilizing paraffin sectioning and H&E staining, we can observe the skull structure of control mice and P0-Cre;caBmpr1a mice, including the posterior frontal suture and cartilage development within. With immunohistochemistry, we will target DDR2 to observe its expansion of DDR2+ cells during the PF suture development. Through TUNEL staining, we can better understand the role of apoptosis in the development and closure of the PF suture through observing regions of cell death. In the future we hope to augment cartilage formation through conducting PF suture-specific enhancement of BMP signaling, allowing us to specify conclusions regarding the nature of craniosynostosis and construct more targeted, less invasive methods of treatment.
