Friday, April 19, 2024
4/19/2024
PROJECT SUMMARY Development of the central nervous system (CNS) requires precise intercellular ‘crosstalk’ between neural cells and non-neural cells. Fibroblasts in the meninges are a non-neural cell that substantially influences brain development, in large part via secreted factors that guide neuronal migration and neurogenesis. This is underscored by significant defects in CNS development observed in mice and humans with mutations in FOXC1, a transcription factor expressed by meningeal fibroblasts but not any neural cells. However much remains unknown about how factors from the meninges activate or inhibit molecular signaling pathways in neural cells to influence developmental processes. Filling these gaps in knowledge would significantly improve our understanding of the homeostatic function of the meninges and the pathology that occurs in neurodevelopmental disorders. Foxc1 mutants do not have normal meningeal fibroblasts over the forebrain, have increased apical progenitor self-renewal and reduced neuron production leading to neocortical lengthening, linked in part to lack of meninges derived retinoic acid. However, it is not known what aberrant signaling pathways in Foxc1 mutant apical progenitors promote increased self-renewal and how this is connected to a reduction of meninges derived factors like retinoic acid. The objective of this proposal is to investigate how meninges derived factors regulate molecular signaling to control neurogenesis in the neocortex. Using spatial transcriptomics on embryonic Foxc1- KO tissue sections, I have identified elevated Notch signaling, known to promote stem cell self-renewal, in Foxc1- KO neocortical progenitors. In Aim 1, I will use global and targeted approaches to inhibit Notch signaling in Foxc1-KO animals and test if this improves neocortical neurogenesis in these mutants. In Aim 2, I will test is meningeal derived retinoic acid or other factors produced by the meninges modulate Notch signaling in neocortical progenitors to promote neurogenesis. Results from this project will provide important insight into molecular mechanisms for meninges-brain signaling required for normal development.
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