Investigating the role of AP-1 during… (F31DE036094) – Project Grant to The Trustees Of Columbia…

Abstract: Ligaments are dense connective tissue structures that provide stability to joints and enable movement. Ligament injury induces a healing response that is characterized by the formation of a fibrotic scar. This scar tissue is often weaker and lacks the biochemical and biomechanical properties of the native structure. To date, there are no effective treatment strategies that can promote a regenerative response to repair ligaments following injury. To enhance ligament healing, IT is important to understand the cellular mechanisms that promote scar- free ligament regeneration. Our lab has developed a novel injury model to study scar-free ligament regeneration by utilizing the highly regenerative zebrafish as a model organism. We demonstrate that zebrafish have the capacity to regenerate their craniofacial interopercular mandibular (IOM) ligament following transection without forming a fibrotic scar. Craniofacial ligament regeneration in zebrafish is driven by a series of fate changes where pre-existing ligamentocytes in the left-over ligament stubs lose their ligament cell fate characteristics and undergo dedifferentiation. Dedifferentiated ligamentocytes give rise to a regenerative mesenchymal cell population that bridges the injury GAP then undergoes redifferentiation by reestablishing ligament cell fate. Our single nuclei assay for transposase accessible chromatin sequencing (snatac-SEQ) dataset derived from cranial neural crest derived cells reveal that regions with increased accessibility in ligamentocytes and regenerative mesenchymal cells after injury have enriched transcription factor binding sites corresponding to AP-1, FOS::JUN motifs. AP-1 transcription factors consist primarily of FOS and JUN proteins and are immediate-early genes that are expressed after connective tissue injury in poorly regenerative species. Preliminary experiments demonstrate that the phosphorylation of JUN increases following ligament injury. This suggests JUN is transcriptionally active and likely forming complexes with FOS proteins. Furthermore, inhibition of JUN phosphorylation prevents ligamentocyte dedifferentiation. This preliminary data showcases an important role of AP-1 during the early stages of ligament regeneration. However, the role of AP-1 during regeneration in during connective tissue regeneration in zebrafish and scar formation in poorly regenerative species remain unclear. To further investigate the role of AP-1 during ligament regeneration, i aim to utilize chemical and genetic approaches to test the requirement of AP-1 for craniofacial ligament regeneration. Additionally, i aim to identify novel targets of AP-1 whose activation is specific to zebrafish ligament regeneration but remain inactive during scarred connective tissue healing. Through combined genetic and cross species analysis, we will provide a broad mechanistic insight as to how AP-1 functions during zebrafish craniofacial ligament regeneration and how IT differs in the context of scarred connective tissue healing in poorly regenerative species. This study will impact our understanding of transcriptional networks governing ligament regeneration and will aid in developing effective treatment strategies to improve the regenerative capacity of connective tissues.

Investigating the role of AP-1 during craniofacial ligament regeneration

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