The role of ependymal cells in regulation of homeostasis in the forebrain

A longstanding interest in our lab has been to study mechanisms that regulate the development of the adult neural stem cell niche in the subventricular zone of the postnatal and adult brain. We discovered that a key gene encoding lipidaging-698x393for the transcription factor Foxj1 is critical for the specification of the neural stem cell niche in the SEZ (Jacquet et al., Development, 2009). Our findings indicated that Foxj1 functions within a temporal framework to specify ependymal cells, a small subset of astrocytes, and intriguingly a novel and unique population of olfactory bulb neuronal subtype at distinct time points during late embryogenesis and early postnatal life (Jacquet et al., J. Neurosci., 2011). We discovered that at least a subset of Foxj1-derived cells are secretory cells that regulate the maturation of nearby progenitors and olfactory bulb neurons in a non-autonomous manner. These functions appear to be Foxj1-dependent, a concept that expands beyond the well-known canonical role of Foxj1 in genesis of motile cilia in subsets of epithelial cells throughout the body. As with many research projects, our studies with Foxj1 led to a number of novel and unexpected discoveries which changed the trajectory of the project over the last decade. We homed in on candidate mechanisms that may regulate secretion from Foxj1+ cells using state-of-the-art genetic tools developed in our laboratory combined with high throughput screening methods. Exciting data showed that a protein called MARCKS dynamically functions as a chaperone for granule containing vesicles in ependymal cells. It turns out these granules are Mucin associated, which is a completely novel concept in the field of neurobiology. Remarkably, conditional (selective) knockout of MARCKS in the Foxj1-derived lineage (largely ependymal cells) results in changes that resemble precocious aging of the brain including changes in Mucin availability and distribution in the interstitial spaces of the forebrain (Muthusamy et al., Aging Cell, 2015). The laboratory is intensely focused on identify the precise source of Mucins and their targets in the CNS interstitium, and their role in regulation of CNS and behavioral aging. (Supported by NIH R01 NS098370)