The Role of Foxg1 in the Development of Neural Stem Cells of the Olfactory Epithelium

Abstract

The olfactory epithelium (OE) of the mouse is an excellent model system for studying principles of neural stem cell biology because of its well-defined neuronal lineage and its ability to regenerate throughout life. To approach the molecular mechanisms of stem cell regulation in the OE, we have focused on Foxg1, also known as brain factor-1, which is a member of the Forkhead transcription factor family. Foxg1 −/− mice show major defects in the OE at birth, suggesting that Foxg1 plays an important role in OE development. We find that Foxg1 is expressed in cells within the basal compartment of the OE, the location where OE stem and progenitor are known to reside. Since FoxG1 is known to regulate proliferation of neuronal progenitor cells during telencephalon development, we performed BrdU pulse-chase of Sox2-expressing neural stem cells during primary OE neurogenesis. We found the percentage of Sox2-expressing cells that retained BrdU was twice as high in Foxg1 −/− OE as in wildtypes, suggesting that these cells are delayed and/or halted in their development in the absence of Foxg1. Our findings suggest that the proliferation and/or subsequent differentiation of Sox2-expressing neural stem cells in the OE are regulated by Foxg1. KeywordsMouse; neurogenesis; olfactory epithelium; neuronal progenitor; neural stem cell; proliferation; Forkhead; transcription factor; BrdU; Mash1; Ngn1; Sox2; TGF-β; FGF; olfactory receptor neuron The OE neural stem cellIn the past decade, increasing attention has been paid to address the question of how cellautonomous and non-autonomous molecular mechanisms interact to control neurogenesis 1 -5. Such information is of particular importance for understanding the behavior of stem cells in the context of their use as a potential source of treatment for injured or diseased nervous system tissue.In order to understand the basic principles that govern the generation and regeneration of neurons in the mammals, we have studied the molecular regulation of neurogenesis in a well-characterized neurogenic epithelium, the olfactory epithelium (OE) of the mouse 1 , 3. We use OE as a model system, both because of its capacity for continual neurogenesis 6, Each stage of neurogenesis is defined both by the expression of particular marker genes and by a generally consistent histological arrangement of the cells within the OE, which becomes apparent after about day 14 of gestation in the mouse 21 -23. Studies suggest that stem and TA progenitors are components of the so-called "globose" basal cell (GBC) population, and reside in the basal compartment of the OE atop the "horizontal" basal cells which are adjacent to the basal lamina 1 , 5 , 18 , 24. Once TA progenitors commit to the ORN lineage and undergo postmitotic differentiation, the immature ORNs start migrating from the basal compartment toward a more apical position in the OE, and finally become the bipolar mature ORNs, extending dendrites to the nasal cavity and axons through the OE to the olfactory bulb (Figure 1).The OE also provides a ...

Olfactory sensory system develops from coordinated movements within the neural plate

“…As part of anterior neural plate pattern patterning several transcription factors are expressed in the olfactory sensory system, including the future telencephalon and OP. The Foxg1 transcription factor is expressed in both the olfactory sensory precursors and telencephalic precursors in both mouse and zebrafish (Danesin et al, 2009; Kawauchi et al, 2009; Danesin and Houart, 2012; Zhao et al, 2009). The loss of function of Foxg1 in knock-out mice leads to loss of the entire olfactory system including the OE, bulb and vomeronasal organ (Duggan et al, 2008).…”

FoxG1 Promotes the Survival of Postmitotic Neurons

“…In addition to regulating proliferation, differentiation, and possibly survival of neural progenitor cells, FoxG1 promotes axonal growth in the developing retina (Xuan et al, 1995; Trejo et al, 2004; Picker et al, 2009), regulates patterning of the developing forebrain (Xuan et al, 1995; Danesin et al, 2009), and is necessary for the proper formation of the inner ear (Pauley et al, 2006; Hwang et al, 2009), as well as the olfactory system (Duggan et al, 2008; Kawauchi et al, 2009a,b). Several recent studies have found that FoxG1 mutations are associated with the congenital form of Rett syndrome, a severe neurodevelopmental disorder (Jacob et al, 2009; Mencarelli et al, 2009, 2010; Philippe et al, 2010).…”

Emx2 and Foxg1 Inhibit Gliogenesis and Promote Neuronogenesis

“…Foxg1 encodes for a winged-helix TF expressed by rostral CNS and sense organs, crucial for their morphogenesis [43][44][45][46][47][48]. It is involved in several aspects of telencephalic development, including specification of the telencephalic field [49], specification of basal ganglia, paleo-and neo-cortex [48,50,51], and cortical laminar specification [21,52].…”