Defective Forebrain Development in Mutant Mice

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Investigator: Samuel Pleasure, MD, PhD
Sponsor: NIH National Institute on Drug Abuse

Location(s): United States

Description

During the entire course of cortical development neuroepithelial stem cells and later the RG maintain constant cellular contact with meningeal cells lining the surface of the developing cortex. Meningeal fibroblasts generate the basement membrane (BM) covering the cortex, and it has long been known that destruction of the meninges or the BM has substantial consequences for cortical development. We have uncovered evidence that defects in the meningeal developmental program caused by mutation of a transcriptional regulator of meningeal development have major consequences for cortical development by disrupting neuronal progenitor proliferation. Our identification of major consequences for cortical neurogenesis due to meningeal defects has led us to develop the main hypothesis of this proposal - that the meninges are a signaling center producing soluble ligands regulating the onset of neocortical neurogenesis. I will address this idea in two aims designed first to characterize the signaling roles of the meninges and second to examine the complex development of the meninges: Aim 1: Examine the signaling role of the meninges on neocortical neurogenesis. One of the most exciting phenotypes in the Foxc1 mutant mice is the apparent failure of neuroepithelial progenitors to properly regulate cell cycle exit and switch to producing neurons. These findings are consistent with the idea that the meninges control the onset and progression of neocortical neurogenesis. We have also now identified the probable meningeally produced factor responsible for the neurogenic switch, and I propose experiments to further establish this finding. I will also proceed with our plan of identifying additional secreted meningeally produced factors that might be responsible additional signaling roles of the meninges. Aim 1a: Characterize the developmental anatomic basis of the Foxc1 mutant neurogenic phenotype. Aim 1b: Determine whether Retinoic Acid (RA), produced by the cortical meninges, regulates the onset and progression of cortical neurogenesis by acting as a diffusible signal. Aim 1c: Use a candidate approach and expression profiling to identify additional meningeally produced factors that regulate cortical neurogenesis. Aim 2: Characterize the differentiation program of the embryonic cortical meninges. Our identification of novel signaling roles for the meninges suggests that further examination of the details how its signaling capacity appears would be of importance. The cortical meninges are formed by a migration of cranial neural crest cells to cover the cortex at about E10. Previous studies have not characterized the developmental events that control this complex migration, or even the details of embryonic meningeal cell phenotype. We have now identified at least four distinct cell types that contribute to the cortical meninges at E12.5, at least two of which are responsible for producing specific secreted signals controlling cortical development (Cxcl12 and RA). This aim will characterize the cellular development of the meninges and will determine whether, as previously proposed, all layers of the cortical meninges develop from a primitive group of meningeal fibroblasts, or whether distinct subsets of these cells migrate in separate streams from cranial neural crest. In addition, we will characterize the developmental function of Foxc1 in the meninges in regulating these events. Understanding the mechanisms governing the development of the cerebral cortex is one of the central goals of developmental neurobiology and it is abundantly clear that there are a host of human conditions that are impacted by defects in cortical development, including epilepsy, mental retardation, schizophrenia and autism. In addition, in recent years it has become apparent that cortical development and function are also related to many of the things that make us most human - emotion, drive, impulsivity, etc. Despite the fundamental importance of cortical development there remain major questions about the key regulatory events that shape the formation of the brain. In this proposal we explore a novel hypothesis strongly based in our preliminary data. We test the proposition that the meningeal coverings of the brain play a fundamental role in the development of the cortex, controlling many aspects of cortical progenitor behavior by the release of soluble factors that signal to the developing cortex.