Investigating the Regulatory Logic Underlying Meningeal Development and Tumorigenesis - PROJECT SUMMARY The cranial neural crest (NC) contributes to the formation of many craniofacial structures including the bones and cartilage of the face, tooth dentin, peripheral ganglia, and the meninges. In the context of craniofacial biology, the cranial meninges provide osteogenic signals, instruct calvarial patterning, and morphogenesis, maintain cranial suture patency, and act as stem cell reservoirs, essentially regulating the development of these structures. During early embryogenesis, mesenchyme cells derived from the NC and mesoderm surround the brain and establish a mesenchymal sheath, the primitive meninx, which serves as the primordium for the meninges, skull, and scalp. The primitive meninx will eventually form the tri-layered meningeal structure – dura, arachnoid, and pia mater. In amniotes, the cranial NC gives rise to the forebrain's meninges, whereas the midbrain and hindbrain meninges are mesoderm-derived. Unfortunately, the gene regulatory networks (GRNs) deployed for early meningeal development and why the dichotomy exists in the case of meninges origin are poorly understood. Defects in NC development lead disorders, termed “neurocristopathies”, that include Treacher Collins syndrome, craniosynostosis, 3MC syndrome, Meckel-Gruber syndrome, and Pfeiffer syndrome which present with improperly/abnormally fused skulls and incompletely formed skulls. Whether these defects arise as a result of improperly formed meninges is still underexplored. Moreover, abnormal proliferation of meninges sporadically or due to cranial radiotherapy and genetic disorder Neurofibromatosis type II can lead to the formation of pediatric and adult meningiomas. My preliminary studies have identified that NC/mesoderm origins of the meninges are conserved in zebrafish and developed an inducible meningioma model. With this Pathway to Independence Award, I will seek to explore and understand the underlying mechanisms of meningeal development and tumorigenesis. The overall objectives of this proposal are to dissect the spatiotemporal heterogeneity and plasticity of the cranial meninges using single-cell (sc)-multi-omics, whole animal live imaging, and tissue-specific ablation (Aim1), functionally characterize the GRNs involved in meningeal development (Aim2), and determine the developmental GRNs activated in cranial meningiomas (Aim3). The work proposed in this Pathway to Independence Award proposal will be greatly facilitated by my multi-disciplinary advisory committee with expertise in single-cell RNA-seq approaches/analyses, functional genomics, and live imaging. After developing a formidable skillset and research foundation afforded by the two years of the mentored phase of this award in Dr. Marianne Bronner’s lab at the California Institute of Technology, my goal is to establish a high-impact, independent research group that will combine systems-level approaches with state-of-the-art cell and developmental biology techniques to address questions of tumorigenesis through a developmental lens. Long- term project hypotheses are focused on delineating tissue-level interactions between the meninges and the skull during development and tumorigenesis.
