The regenerative capacity of many placode-derived epithelial structures makes them of interest for understanding the molecular control of epithelial stem cells and their niches. Here, we investigate the interaction between the developing epithelium and its surrounding mesenchyme in one such system, the taste papillae and sensory taste buds of the mouse tongue. We identify follistatin (FST) as a mesenchymal factor that controls size, patterning and gustatory cell differentiation in developing taste papillae. FST limits expansion and differentiation of Sox2-expressing taste progenitor cells and negatively regulates the development of taste papillae in the lingual epithelium: in Fst -/-tongue, there is both ectopic development of Sox2-expressing taste progenitors and accelerated differentiation of gustatory cells. Loss of Fst leads to elevated activity and increased expression of epithelial Bmp7; the latter effect is consistent with BMP7 positive autoregulation, a phenomenon we demonstrate directly. We show that FST and BMP7 influence the activity and expression of other signaling systems that play important roles in the development of taste papillae and taste buds. In addition, using computational modeling, we show how aberrations in taste papillae patterning in Fst -/-mice could result from disruption of an FST-BMP7 regulatory circuit that normally suppresses noise in a process based on diffusion-driven instability. Because inactivation of Bmp7 rescues many of the defects observed in Fst -/-tongue, we conclude that interactions between mesenchyme-derived FST and epithelial BMP7 play a central role in the morphogenesis, innervation and maintenance of taste buds and their stem/progenitor cells.

A critical analysis of the investigations to date indicates the data are not quantitatively impressive and raises substantial questions about the clinical importance of the hypocholesterolemic effects observed.

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 ...

Stem cell therapies to treat central nervous system (CNS) injuries and diseases face many obstacles, one of which is the fact that the adult CNS often presents an environment hostile to the development and differentiation of neural stem and progenitor cells. Close examination of two regions of the nervous system -the olfactory epithelium (OE), which regenerates, and the neural retina, which does not -have helped identify endogenous signals, made by differentiated neurons, which act to inhibit neurogenesis by stem/progenitor cells within these tissues. In this chapter, we provide background information on these systems and their neurogenic signaling systems, with the goal of providing insight into how manipulation of endogenous signaling molecules may enhance the efficacy of stem cell neurotherapeutics.

proliferation but did not change the level of apoptosis. Furthermore we identified two targets of TBX22 that could be mediating the phenotype, DLX5 and MSX2. We have therefore demonstrated novel functions for TBX22, a gene that causes some forms of human orofacial clefting. This work was funded by CIHR grants to JMR.