title: Tox: a multifunctional transcription factor and novel regulator of mammalian corticogenesis.
abstract: Major efforts are invested to characterize the factors controlling the proliferation of neural stem cells. During mammalian corticogenesis, our group has identified a small pool of genes that are transiently downregulated in the switch of neural stem cells to neurogenic division and reinduced in newborn neurons. Among these switch genes, we found Tox, a transcription factor with hitherto uncharacterized roles in the nervous system. Here, we investigated the role of Tox in corticogenesis by characterizing its expression at the tissue, cellular and temporal level. We found that Tox is regulated by calcineurin/Nfat signalling. Moreover, we combined DNA adenine methyltransferase identification (DamID) with deep sequencing to characterize the chromatin binding properties of Tox including its motif and downstream transcriptional targets including Sox2, Tbr2, Prox1 and other key factors. Finally, we manipulated Tox in the developing brain and validated its multiple roles in promoting neural stem cell proliferation and neurite outgrowth of newborn neurons. Our data provide a valuable resource to study the role of Tox in other tissues and highlight a novel key player in brain development.
authors.affiliation: DFG-Research Center for Regenerative Therapies, Cluster of Excellence, TU-Dresden, Dresden, Germany.
authors.forename: Benedetta
authors.initials: B
authors.lastname: Artegiani
authors.affiliation: Deep Sequencing Group-SFB655, Biotechnology Center, TU-Dresden, Dresden, Germany.
authors.forename: Antonio M
authors.initials: AM
authors.lastname: de Jesus Domingues
authors.affiliation: DFG-Research Center for Regenerative Therapies, Cluster of Excellence, TU-Dresden, Dresden, Germany.
authors.forename: Sara
authors.initials: S
authors.lastname: Bragado Alonso
authors.affiliation: DFG-Research Center for Regenerative Therapies, Cluster of Excellence, TU-Dresden, Dresden, Germany.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Brandl
authors.affiliation: DFG-Research Center for Regenerative Therapies, Cluster of Excellence, TU-Dresden, Dresden, Germany.
authors.forename: Simone
authors.initials: S
authors.lastname: Massalini
authors.affiliation: Deep Sequencing Group-SFB655, Biotechnology Center, TU-Dresden, Dresden, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Dahl
authors.affiliation: DFG-Research Center for Regenerative Therapies, Cluster of Excellence, TU-Dresden, Dresden, Germany federico.calegari@crt-dresden.de.
authors.forename: Federico
authors.initials: F
authors.lastname: Calegari
mesh_terms: D000818:Animals; D019703:Calcineurin / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation / Q000502:physiology; D002540:Cerebral Cortex / Q000166:cytology / Q000196:embryology*; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D018398:Homeodomain Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism*; D058953:Neural Stem Cells / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D055748:SOXB1 Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology*; D015265:Site-Specific DNA-Methyltransferase (Adenine-Specific) / Q000235:genetics / Q000378:metabolism; D020825:T-Box Domain Proteins / Q000096:biosynthesis / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis / Q000235:genetics; D000098551:Prospero-Related Homeobox 1 Protein
chemical_list: C491198:Eomes protein, mouse; D018398:Homeodomain Proteins; D050778:NFATC Transcription Factors; C493241:Rhox8 protein, mouse; D055748:SOXB1 Transcription Factors; C527783:Sox2 protein, mouse; D020825:T-Box Domain Proteins; D025521:Tumor Suppressor Proteins; D000098551:Prospero-Related Homeobox 1 Protein; D015265:Site-Specific DNA-Methyltransferase (Adenine-Specific); D019703:Calcineurin
keywords: DamID sequencing; HMG‐box transcription factors; Tox; brain development; neural stem cells