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MyT1 Counteracts the Neural Progenitor Program to Promote Vertebrate Neurogenesis
Publication . Vasconcelos, Francisca F.; Sessa, Alessandro; Laranjeira, Cátia; Raposo, Alexandre A.S.F.; Teixeira, Vera; Hagey, Daniel W.; Tomaz, Diogo M.; Muhr, Jonas; Broccoli, Vania; Castro, Diogo S.
The generation of neurons from neural stem cells requires large-scale changes in gene expression that are controlled to a large extent by proneural transcription factors, such as Ascl1. While recent studies have characterized the differentiation genes activated by proneural factors, less is known on the mechanisms that suppress progenitor cell identity. Here, we show that Ascl1 induces the transcription factor MyT1 while promoting neuronal differentiation. We combined functional studies of MyT1 during neurogenesis with the characterization of its transcriptional program. MyT1 binding is associated with repression of gene transcription in neural progenitor cells. It promotes neuronal differentiation by counteracting the inhibitory activity of Notch signaling at multiple levels, targeting the Notch1 receptor and many of its downstream targets. These include regulators of the neural progenitor program, such as Hes1, Sox2, Id3, and Olig1. Thus, Ascl1 suppresses Notch signaling cell-autonomously via MyT1, coupling neuronal differentiation with repression of the progenitor fate.
The multifaceted Foxp3fgfp allele enhances spontaneous and therapeutic immune surveillance of cancer in mice
Publication . Almeida-Santos, Jose; Bergman, Marie-Louise; Jocelyne, Demengeot; Correia, Vasco; Caramalho, Iris; Cabral, Ines
It is well established that therapeutic impairment of Foxp3+ Treg in mice and humans favors immune rejection of solid tumors. Less explored is the impact Foxp3 allelic variants may have on tumor incidence, progression and therapy. In this work, we tested and demonstrate that the Foxp3fgfp reporter allele, found previously to either enhance or reduce Treg function in specific autoimmunity settings, confers increased anti-tumor immunity. Our conclusions stem out of the analysis of three tumor models of different tissue origin, in two murine genetic backgrounds. When compared to wild type animals, mice carrying the Foxp3fgfp allele spontaneously delay, reduce or prevent primary tumor growth, decrease metastasis growth, and potentiate the response to anti-CTLA4 monotherapy. These findings suggest allelic variances at the Foxp3 locus may serve as predictive indicators for personalized therapy and prognostics, and point at possible new therapeutic targets.
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Funding agency
Fundação para a Ciência e a Tecnologia
Funding programme
5876
Funding Award Number
UID/Multi/04555/2013