Stem Cells & Neurogenesis
Neurons are the fundamental units of our nervous system. Neurons are generated from multipotent neural stem cells located in germinal layers of embryonic brain and spinal cord, and in restricted niches in the adult mammalian brain. We investigate how neurogenesis is governed by gene regulatory networks (GRNs) that operate in neural stem cells, and how these can be deployed in disease context such as brain cancer.
Neurons are one of the most complex and diverse cell populations in our body. In spite of this diversity, there are common developmental mechanisms that underlie the generation of virtually every neuron. Our work aims at deciphering such regulatory logic, while studying the transcriptional pathways that control the balance between self-renewal and differentiation of neural stem cells. A major focus of our past and current work has been on pan-neuronal regulators, such as the proneural factor Ascl1, the Notch pathway, or the classic EMT inducers of the ZEB family of transcription factors. Another goal of our research is to understand how the regulatory logic observed in development may be used during cell division, as transcription is switched-off in mitosis, and neural-specific gene expression programs need to be reestablished in daughter cells. For this, we study the interplay between transcriptional regulators and chromatin along the cell cycle, and in the context of cell fate changes. Finally, we also address how key regulators of neural development may be hijacked in disease. We focus on Glioblastoma, the most frequent and aggressive brain tumor in adults, containing a population of cancer stem-like cells that exploit developmental pathways to fuel tumor growth and recurrence. Our research has a strong component of genomics, combining techniques such as genome wide-mapping of transcription factors and chromatin landscape profiling, applied to the developing mouse embryo and cellular models. These are complemented with live imaging, cellular and transcriptional assays.
PAD2-Mediated Citrullination Contributes to Efficient Oligodendrocyte Differentiation and Myelination. Cell Reports27(4):1090-1102.e10, 2019. [Journal: Article] [CI: 11] [IF: 8,1]
DOI: 10.1016/j.celrep.2019.03.108 SCOPUS: 85064315917. .
Rosmaninho P., Mükusch S., Piscopo V., Teixeira V., Raposo A.A.S.F., Warta R., Bennewitz R., Tang Y., Herold-Mende C., Stifani S., Momma S., Castro D.S.,
Zeb1 potentiates genome-wide gene transcription with Lef1 to promote glioblastoma cell invasion. EMBO Journal37(15):, 2018. [Journal: Article] [CI: 17] [IF: 11,2]
DOI: 10.15252/embj.201797115 SCOPUS: 85050980313. .
Soares M.A.F., Castro D.S.,
Chromatin immunoprecipitation from mouse embryonic tissue or adherent cells in culture, followed by next-generation sequencing. Methods in Molecular Biology1689:53-63, 2018. [Book Series: Chapter]
DOI: 10.1007/978-1-4939-7380-4_5 SCOPUS: 85031682134. .
Yang S., Toledo E.M., Rosmaninho P., Peng C., Uhlén P., Castro D.S., Arenas E.,
A Zeb2-miR-200c loop controls midbrain dopaminergic neuron neurogenesis and migration. Communications Biology1(1):, 2018. [Journal: Article] [CI: 4]
DOI: 10.1038/s42003-018-0080-0 SCOPUS: 85064037448. .
Vasconcelos F.F., Sessa A., Laranjeira C., Raposo A.A.S.F., Teixeira V., Hagey D.W., Tomaz D.M., Muhr J., Broccoli V., Castro D.S.,
MyT1 Counteracts the Neural Progenitor Program to Promote Vertebrate Neurogenesis. Cell Reports17(2):469-483, 2016. [Journal: Article] [CI: 32] [IF: 8,3]
DOI: 10.1016/j.celrep.2016.09.024 SCOPUS: 85003935959. .
One more factor joins the plot: Pbx1 regulates differentiation and survival of midbrain dopaminergic neurons. EMBO Journal35(18):1957-1959, 2016. [Journal: Note] [CI: 1] [IF: 9,8]
DOI: 10.15252/embj.201695353 SCOPUS: 84997824488. .
Singh S., Howell D., Trivedi N., Kessler K., Ong T., Rosmaninho P., Raposo A.A.S.F., Robinson G., Roussel M.F., Castro D.S., Solecki D.J.,
Zeb1 controls neuron differentiation and germinal zone exit by a mesenchymal-epithelial-like transition. eLife5(MAY2016):, 2016. [Journal: Article] [CI: 29] [IF: 7,7]
DOI: 10.7554/eLife.12717 SCOPUS: 84971612316. .
Raposo A.A.S.F., Vasconcelos F.F., Drechsel D., Marie C., Johnston C., Dolle D., Bithell A., Gillotin S., van den Berg D.L.C., Ettwiller L., Flicek P., Crawford G.E., Parras C.M., Berninger B., Buckley N.J., Guillemot F., Castro D.S.,
Ascl1 coordinately regulates gene expression and the chromatin landscape during neurogenesis. Cell Reports10(9):1544-1556, 2015. [Journal: Article] [CI: 76] [IF: 7,9]
DOI: 10.1016/j.celrep.2015.02.025 SCOPUS: 84931281902. .
Vasconcelos F.F., Castro D.S.,
Transcriptional control of vertebrate neurogenesis by the proneural factor ascll. Frontiers in Cellular Neuroscience8(DEC):, 2014. [Journal: Article] [CI: 31] [IF: 4,3]
DOI: 10.3389/fncel.2014.00412 SCOPUS: 84914172949. .
Wapinski O.L., Vierbuchen T., Qu K., Lee Q.Y., Chanda S., Fuentes D.R., Giresi P.G., Ng Y.H., Marro S., Neff N.F., Drechsel D., Martynoga B., Castro D.S., Webb A.E., Südhof T.C., Brunet A., Guillemot F., Chang H.Y., Wernig M.,
XHierarchical mechanisms for direct reprogramming of fibroblasts to neurons. Cell155(3):621, 2013. [Journal: Article] [CI: 308] [IF: 33,1]
DOI: 10.1016/j.cell.2013.09.028 SCOPUS: 84886784309. .