[Show abstract][Hide abstract] 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 cells are known to reside. Since FoxG1 is known to regulate proliferation of neuronal progenitor cells during telencephalon development, we performed bromodeoxyuridine pulse-chase labeling of Sox2-expressing neural stem cells during primary OE neurogenesis. We found the percentage of Sox2-expressing cells that retained bromodeoxyuridine was twice as high in Foxg1(-/-) OE cells as in the wild type, 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 is regulated by Foxg1.
Annals of the New York Academy of Sciences 08/2009; 1170:21-7. · 4.38 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: MASH1, a basic helix-loop-helix transcription factor, is widely expressed by neuronal progenitors in the CNS and PNS, suggesting that it plays a role in the development of many neural regions. However, in mice lacking a functional Mash1 gene, major alterations have been reported in only a few neuronal populations; among these is a generalized loss of olfactory receptor neurons of the olfactory epithelium. Here, we use a transgenic reporter mouse line, in which the cell bodies and growing axons of subsets of central and peripheral neurons are marked by expression of a tau-lacZ reporter gene (the Tattler-4 allele), to look both more broadly and deeply at defects in the nervous system of Mash1-/- mice. In addition to the expected lack of olfactory receptor neurons in the main olfactory epithelium, developing Mash1-/-;Tattler-4+/- mice exhibited reductions in neuronal cell number in the vomeronasal organ and in the olfactory bulb; the morphology of the rostral migratory stream, which gives rise to olfactory bulb interneurons, was also abnormal. Further examination of cell proliferation, cell death, and cell type-specific markers in Mash1-/- animals uncovered parallels between the main olfactory epithelium and the vomeronasal organ in the regulation of sensory neuron development. Interestingly, this analysis also revealed that, in the olfactory epithelium of Mash1-/- animals, there is an overproduction of proliferating cells that co-express markers of both neuronal progenitors and supporting cells. This finding suggests that olfactory receptor neurons and olfactory epithelium supporting cells may share a common progenitor, and that expression of Mash1 may be an important factor in determining whether these progenitors ultimately generate neurons or glia.
Journal of Neuroscience 04/2003; 23(5):1769-80. · 6.91 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In the olfactory epithelium (OE), generation of new neurons by neuronal progenitors is inhibited by a signal from neurons themselves. Here we provide evidence that this feedback inhibitory signal is growth and differentiation factor 11 (GDF11). Both GDF11 and its receptors are expressed by OE neurons and progenitors, and GDF11 inhibits OE neurogenesis in vitro by inducing p27(Kip1) and reversible cell cycle arrest in progenitors. Mice lacking functional GDF11 have more progenitors and neurons in the OE, whereas mice lacking follistatin, a GDF11 antagonist, show dramatically decreased neurogenesis. This negative autoregulatory action of GDF11 is strikingly like that of its homolog, GDF8/myostatin, in skeletal muscle, suggesting that similar strategies establish and maintain proper cell number during neural and muscular development.
[Show abstract][Hide abstract] ABSTRACT: The olfactory epithelium of the mouse has many properties that make it an ideal system for studying the molecular regulation of neurogenesis. We have used a combination of in vitro and in vivo approaches to identify three distinct stages of neuronal progenitors in the olfactory receptor neuron lineage. The neuronal stem cell, which is ultimately responsible for continual neuron renewal in this system, gives rise to a transit amplifying progenitor identified by its expression of a transcription factor, MASH1. The MASH1-expressing progenitor gives rise to a second transit amplifying progenitor, the Immediate Neuronal Precursor, which is distinct from the stem cell and MASH1-expressing progenitor, and gives rise quantitatively to olfactory receptor neurons. Regulation of progenitor cell proliferation and differentiation occurs at each of these three cell stages, and growth factors of the fibroblast growth factor (FGF) and bone morphogenetic protein (BMP) families appear to play particularly important roles in these processes. Analyses of the actions of FGFs and BMPs reveal that negative signaling plays at least as important a role as positive signaling in the regulation of olfactory neurogenesis.
Microscopy Research and Technique 09/2002; 58(3):176-88. · 1.59 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The basic helix-loop-helix transcription factor neurogenin1 is required for proper nervous system development in vertebrates. It is expressed in neuronal precursors during embryonic development and is thought to play a role in specifying neuronal fate. To investigate the regulation of neurogenin1 expression, the transcriptional start site of the gene was identified and a 2.7-kb fragment ending in the first exon was shown to possess basal promoter activity. This 2.7-kb fragment was able to promote expression of reporter genes in P19 cells under conditions in which expression of endogenous neurogenin1 was induced. Importantly, the 2.7-kb fragment was able to drive expression of a lacZ reporter gene in transgenic mice in most tissues in which neurogenin1 is normally expressed, including those peripheral ganglia that fail to develop in neurogenin1 "knockout" mice. These findings identify a regulatory region containing elements responsible for appropriate expression of a gene with a crucial role in generating the vertebrate nervous system.