title: Generation of Cajal-Retzius neurons in mouse forebrain is regulated by transforming growth factor beta-Fox signaling pathways.
abstract: The generation of Cajal-Retzius (CR) neurons is restricted to discrete sites in the telencephalon. Most of these sites do not express Foxg1, a transcription factor that inhibits transforming growth factor (TGF)beta-dependent upregulation of p21. We tested the hypothesis that TGFbeta signaling triggers CR neurogenesis in Foxg1-deficient zones through p21 induction. In Foxg1(+/+) mice, p21 (a) was expressed in select cycling cells in CR neuron-producing areas and (b) was co-localized in newly generated CR neurons. Zones of CR neuronal production and p21 expression were expanded in the forebrains of Foxg1(Cre/Cre) mice. Manipulation of TGFbeta signaling in explants from cortical hems of wild-type mice altered p21 expression and the production of CR neurons. Furthermore, despite continued TGFbeta activity, p21 immunoreactivity diminished in CR neurons with distance from their generation site. This implicated a second pathway controlling p21 expression. We provide evidence that Foxo3a, which has been shown to translocate into the nucleus to act as a transcriptional co-activator of TGFbeta-dependent upregulation of p21, is strategically expressed to be involved in controlling p21 expression in CR neurons. Specifically, Foxo3a was nuclear in p21+/reelin+ cells in sites of CR neuronal generation, however, nuclear Foxo3a immunoreactivity was absent in p21-/reelin+ cells distal from sites of CR neurogenesis. Thus, TGFbeta and Foxo3a may work in concert to regulate expression of p21 during CR neuronal generation.
authors.affiliation: Department of Neuroscience and Physiology, State University of New York-Upstate Medical University, Syracuse, NY 13210, USA.
authors.forename: Julie A
authors.initials: JA
authors.lastname: Siegenthaler
authors.forename: Michael W
authors.initials: MW
authors.lastname: Miller
mesh_terms: D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000378:metabolism; D005260:Female; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D008297:Male; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism; D000091042:Reelin Protein; D015398:Signal Transduction; D013687:Telencephalon / Q000166:cytology* / Q000196:embryology / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004268:DNA-Binding Proteins; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; C489565:Foxg1 protein, mouse; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D000091042:Reelin Protein; D016212:Transforming Growth Factor beta; C000606368:Trp73 protein, mouse; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins; C000717128:Reln protein, mouse