Foxg1Is Required for Development of the Vertebrate Olfactory System

Abstract

Illuminating the molecular identity and regulation of early progenitor cells in the olfactory sensory epithelium represents an important challenge in the field of neural development. We show in both mouse and zebrafish that the winged helix transcription factor Foxg1 is expressed in an early progenitor population of the olfactory placode. In the mouse, Foxg1 is first expressed throughout the olfactory placode but later becomes restricted to the ventrolateral olfactory epithelium. The essential role of Foxg1 in olfactory development is demonstrated by the strikingly severe phenotype of Foxg1 knock-out mice: older embryos have no recognizable olfactory structures, including epithelium, bulb, or vomeronasal organs. Initially, a small number of olfactory progenitors are specified but show defects in both proliferation and differentiation. Similarly, antisense RNA knockdown of Foxg1 expression in the zebrafish shows a reduction in the number of neurons and mitotic cells in olfactory rosettes, mirroring the phenotype seen in the mouse Foxg1 null mutant. Using mosaic analysis in the zebrafish, we show that Foxg1 is required cell-autonomously for the production of mature olfactory receptor neurons. Therefore, we identified an evolutionarily conserved requirement for Foxg1 in the development of the vertebrate olfactory system.

Foxg1promotes olfactory neurogenesis by antagonizingGdf11

“…3). Recent studies in the zebrafish, in which morpholino oligonucleotides were used to reduce Foxg1 levels in a mosaic fashion (Duggan et al, 2008), also showed that Foxg1 influences OE neurogenesis in a cellautonomous fashion, a result opposite to what would have been expected if Foxg1 acts by controlling the expression of a secreted growth factor, such as an FGF.…”

“…Foxg1 cre/+ mice, in which the Foxg1 coding sequence is replaced by the gene encoding Cre-recombinase (Cre) (Hebert and McConnell, 2000), were maintained on an outbred Swiss Webster background (Harlan, Indianapolis, IN, USA). Although expression of Cre recombinase in the Foxg1 locus has been shown to have some effects on telencephalon development when the allele is maintained on a congenic C57bl/6 background (Eagleson et al, 2007), when maintained on an outbred background, Foxg1 cre/cre mice have been shown to have nervous system phenotypes identical to those observed in another Foxg1 null strain, Foxg1 lacZ/lacZ (Duggan et al, 2008;Eagleson et al, 2007;Hanashima et al, 2007;Martynoga et al, 2005;Muzio and Mallamaci, 2005;Pratt et al, 2004 …”

“…Foxg1 is highly expressed in anterior neural structures, and promotes their development; neural structures whose development is adversely affected in Foxg1 -/-mice include the cerebral cortex, ventral telencephalon, ear, retina and olfactory epithelium (OE) (Duggan et al, 2008;Hanashima et al, 2007;Hanashima et al, 2004;Hebert and McConnell, 2000;Martynoga et al, 2005;Pauley et al, 2006;Pratt et al, 2004;Xuan et al, 1995). In mice that are null for Foxg1, the cerebral hemispheres are dramatically reduced in size, ventral telencephalic structures are lacking, and the animals die at birth (Xuan et al, 1995).…”

Partially redundant proneural function reveals the importance of timing during zebrafish olfactory neurogenesis

“…Indeed, the current model suggests that progenitor cells expressing Ascl1 gives rise to intermediate precursors that require Neurog1 for differentiation (Cau et al, 2002;Cau et al, 1997;Guillemot et al, 1993;Nicolay et al, 2006). More recently, it has been shown that the wingedhelix transcription factor Foxg1 acts upstream of Ascl1 for correct olfactory neurogenesis (Duggan et al, 2008). Similarly, microRNAs of the miR-200 family have been implicated in the maintenance of olfactory neurogenesis (Choi et al, 2008).…”

“…As for correct placode formation at earlier stages, the Cxcl12a-Cxcr4b interaction is required for the proper guidance of pioneer axons (Miyasaka et al, 2007;Yoshihara, 2009); the Robo2 receptor and Slit ligands have also been implicated in fasciculation and guidance of axons of olfactory neurons Yoshihara, 2009). Surprisingly, however, although a requirement for Foxg1 and microRNAs has apparently been conserved between zebrafish and mouse during the early steps of olfactory neurogenesis, nothing is known concerning proneural gene function during the development of either early or late-born olfactory neurons in zebrafish (Choi et al, 2008;Duggan et al, 2008).…”