Generation of Cajal-Retzius neurons in mouse forebrain is regulated by transforming growth factor beta-Fox signaling pathways

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 p2l. We tested the hypothesis that TGF beta signaling triggers CR neurogenesis in Foxg1-deficient zones through p2l induction. In Foxg1(+/+) mice, p2l (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 p2l expression were expanded in the forebrains of Foxg1(Cre/Cre) mice. Manipulation of TGF[3 signaling in explants from cortical hems of wild-type mice altered p2l expression and the production of CR neurons. Furthermore, despite continued TGF beta activity, p2l immunoreactivity diminished in CR neurons with distance from their generation site. This implicated a second pathway controlling p2l expression. We provide evidence that Foxo3a, which has been shown to translocate into the nucleus to act as a transcriptional co-activator of TGF beta-dependent upregulation of p2l, is strategically expressed to be involved in controlling p2l 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 p2l-/reelin+ cells distal from sites of CR neurogenesis. Thus, TGF beta and Foxo3a may work in concert to regulate expression of p2l during CR neuronal generation. (c) 2007 Elsevier Inc. All rights reserved.