**2. Developmental aspects of meninges pertinent to primary ectopic meningiomas and ectopic meningothelial tissue**

This will be a brief section and by no means an exhaustive treatment of the embryological, morphological and molecular genetics aspects of meninges development. For a more thorough review of meninges development, the reader is directed to the excellent reviews by Dasgupta and Jeong [3] and Lopes [4]. However, here, we will attempt to highlight elements of what is known about the embryological and particularly molecular pathways involved in meninges development as it may relate to the development of meningiomas and the presence of meningothelial tissues in other anatomical locations outside of the central nervous system (CNS) proper.

In contrast to other areas of CNS development, relatively little is known about the molecular characteristics of meninges development. In a broad sense, however, the meninges increasingly are being shown to be critical to proper calvarial and underlying brain development. It is noted that the cranial meninges are derived from two cellular pools; the neural crest (ectoderm) and mesoderm. Neural crest derived cells can be found in the three layers of meninges covering the forebrain cerebral hemispheres but not in the meninges covering midbrain or hindbrain. Calvarial development closely parallels meninges development in that the frontal bones are primarily neural crest derived while the parietal bones are of mesodermal origin. Foxc1 is a key and ubiquitously expressed transcription factor in meninges development with noted early upregulation in the primary meninx. Its prominent role is demonstrated by lack of apical arachnoid and dura mater formation as well as lack of apical calvarial development in Foxc1 mutant mice. Parietal bone development appears to depend on the underlying meninges (derived from neural crest) expressing transforming growth factor beta 2 receptor (Tgfbr2) as Tgfbr2 mutant mice show severe defects in both parietal bone and underlying meninges development. The dura or outer dense layer of the meninges becomes closely apposed to the underside of the bony calvarium and is the de facto periosteal layer. The mesenchyme around the developing brain is divided into layers that include a dermal layer (dermis of scalp), skeletogenic layer (skull), and then the meningeal primordium. By extension, it can be plausible that ectopic meningiomas can arise (and indeed do) in the bones of the calvarium and scalp. It has been proposed that arachnoid cells or precursors can migrate with cranial nerves as they exit their foramina during development and be the forerunners of primary ectopic meningiomas in anatomic regions such as the orbit, ear, and neck [1]. Meninges appear to play crucial roles in brain development including providing trophic factors for neuronal survival, migration/positioning of neurons, neuronal generation from neuronal progenitors, blood vessel development, corpus callosum development, and may provide a niche for neural stem cells [5].

Again, by extension, it is not implausible to think that since much of the structures comprising the head and neck are derived from neural crest (and mesenchymal) cells, cells with multipotent capabilities, that some of these cells could be dormant and later directed down a path of meningeal differentiation in aberrant locations.
