Generation of Cajal–Retzius neurons in mouse forebrain is regulated by transforming growth factor β-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)β-dependent upregulation of p21. We tested the hypothesis that TGFβ 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 Foxg1Cre/Cre mice. Manipulation of TGFβ signaling in explants from cortical hems of wild-type mice altered p21 expression and the production of CR neurons. Furthermore, despite continued TGFβ 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 TGFβ-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, TGFβ and Foxo3a may work in concert to regulate expression of p21 during CR neuronal generation.