Olfactory bulb interneurons are made into adulthood by adult neural stem cells. Understanding the molecular control of these cells is crucial to determining if this niche can be used for cell replacement therapies in neurogenerative diseases. Recent work on the specification of olfactory bulb interneurons has identified key factors that regulate their production, migration, and survival. The transcription factor Sp8 has recently been shown to cause selective reduction in the CaIR and GABAergic/nonDA interneurons of the glomerular layer while loss of Pax6 can cause selective loss of DA interneurons. Despite these advancements in our understanding of the molecular control of these progenitor regions, it is still unknown what factors control the generation of CalB positive interneurons. In this study I aim to determine the role of the recently identified winged helix/forkhead transcription factor Foxp2 in the generation of olfactory bulb interneurons. My hypothesis is that Foxp2 is required for the production of CalB expressing interneurons of the olfactory bulb glomerular layer. I will test this hypothesis by accomplishing the following three aims:
Aim 1) To characterize the expression pattern and identity of Foxp2 in olfactory bulb interneurons and their progenitor regions in the embryonic and postnatal brain. Foxp2 is expressed in olfactory bulb interneuron progenitor regions. Unfortunately these regions contain a wide variety of cell types and progenitors and the expression of Foxp2 in these cells remains unknown. In order to determine the identity of these cells I will use multi-labeling immunohistochemistry to determine if these cells colocalize with known markers of olfactory bulb interneuron progenitors as well as markers of mature olfactory bulb interneurons.
Aim 2) To determine what factors regulate the expression of Foxp2. The transcription factors Pax6 and Gsh2 are required for proper development of dorsal-ventral patterning in the embryonic telencephalon while Sp8 and Mashl play important roles in olfactory bulb interneuron generation. In order to determine if Pax6, Gsh2, Sp8 and Mashl regulate Foxp2 expression, I will examine mice that are mutant for these transcription factors. Furthermore, the transcription factors Dlx5/6 have been shown to be expressed in cells that will give rise to olfactory bulb interneurons. I will use fate mapping with Dlx5/6::Cre-lres-EGFP (CIE) and an EGFP reporter mouse to determine if Foxp2 expressing cells arise from this population of progenitors.
Aim 3) To assess the requirement of Foxp2 on the generation of olfactory bulb interneuron subtypes in the glomerular layer. To determine the requirement for Foxp2 in the generation of olfactory bulb interneuron subtypes, I will examine Foxp2 mutant mice. ? ? ?
|Borello, Ugo; Madhavan, Mayur; Vilinsky, Ilya et al. (2014) Sp8 and COUP-TF1 reciprocally regulate patterning and Fgf signaling in cortical progenitors. Cereb Cortex 24:1409-21|
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|Allen 2nd, Zegary J; Waclaw, Ronald R; Colbert, Melissa C et al. (2007) Molecular identity of olfactory bulb interneurons: transcriptional codes of periglomerular neuron subtypes. J Mol Histol 38:517-25|