Gene regulatory networks (GRNs) involved in development of cranial meninges

Cross-section of lamprey larvae labelling the meninges (magenta)

The meninges are membranous layers surrounding the central nervous system. In the craniofacial system, the meninges lie between the brain and the skull and interact closely with both during development. Meninges of the forebrain arise from the neural crest, whereas the mid/hindbrain meninges originate from the mesoderm. Since GRNs of developing meninges are poorly understood, I utilized chromatin accessibility assays coupled with RNA-sequencing of stable transgenic zebrafish lines to generate insights into the migration and differentiation of early meningeal precursors. Importantly, these results set the stage for assessing the meningeal GRNs at the single-cell level. The manuscript is currently being prepared for publication. 

Evolution of meninges in basal vertebrates

Previous studies indicate that the meninges are a vertebrate innovation. It is unclear why there was a need for the dual origin of cranial meninges. I am currently investigating the meningeal origins of the ancient vertebrate Petromyzon marinus (sea lamprey). This work will provide insight into the evolutionary mechanisms involved in the “New-Head Hypothesis” and indicates that the gradual regionalization of meninges onto the forebrain might have played an essential role in the formation and evolution of the vertebrate head. 

Neural crest GRN underlying onset of meningioma 

Neurofibromatosis (NF2) gene single nucleotide variants (SNVs) and small indels are common in cranial meningiomas and are present in 40-50% cases. The neural crest-derived meningioma has a poor prognosis, WHO grade II & III tumors, and rapid recurrence. I have identified that NF2 is expressed during early meningeal development and is critical for their controlled proliferation. Additionally, conditional knockout of zebrafish nf2 leads to the development of cranial meningiomas. This model holds significant potential for facilitating therapeutic screening, elucidating key driver genes implicated in the onset of meningiomas. Currently, I am optimizing targeted nf2 knockout in neural crest and mesoderm-derived meninges. Multi-modal analysis of neural crest and mesoderm-derived meningiomas will help us understand the molecular underpinnings responsible for the aggravated tumorigenesis capabilities of NC-derived meninges.