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Generation of Cajal-Retzius neurons in mouse forebrain is regulated by transforming growth factor beta-Fox signaling
Julie A Siegenthaler1, Michael W Miller
1Department of Neuroscience and Physiology, State University of New York-Upstate Medical University, Syracuse, NY 13210, USA.
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.
Insights
Transforming growth factor-beta (TGFβ) signaling and Foxo3a cooperate to regulate p21 expression, crucial for Cajal-Retzius (CR) neuron generation in specific telencephalic regions.
Area of Science:
- Neuroscience
- Developmental Biology
- Molecular Biology
Background:
- Cajal-Retzius (CR) neurons are essential for cortical development and are generated in specific telencephalic regions.
- Foxg1, a transcription factor, normally inhibits transforming growth factor-beta (TGFβ)-dependent p21 upregulation.
- The precise molecular mechanisms controlling CR neurogenesis, particularly in Foxg1-deficient areas, remain incompletely understood.
Purpose of the Study:
- To investigate the role of TGFβ signaling and p21 in CR neurogenesis within Foxg1-deficient zones.
- To elucidate the involvement of Foxo3a in regulating p21 expression during CR neuron development.
Main Methods:
- Utilized Foxg1(+/+) and Foxg1(Cre/Cre) mouse models to study CR neuron generation and p21 expression.
- Performed manipulation of TGFβ signaling in cortical explants.
- Analyzed the expression and localization of p21 and Foxo3a in CR neurons and adjacent cells.
Main Results:
- CR neuron production and p21 expression were expanded in Foxg1-deficient mice.
- TGFβ signaling manipulation altered p21 expression and CR neuron production in wild-type explants.
- p21 expression decreased with distance from the generation site, suggesting a secondary regulatory pathway.
- Foxo3a nuclear localization was observed in p21+/reelin+ CR neuron progenitor cells, but not in distal p21-/reelin+ cells.
Conclusions:
- TGFβ signaling, in conjunction with Foxo3a, plays a critical role in regulating p21 expression during CR neurogenesis.
- This coordinated action of TGFβ and Foxo3a is vital for controlling p21 levels in developing CR neurons.
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