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.
Function and regulation of transcription factors during mitosis-To-G1 transition. Open Biology12(6):, 2022. [Journal: Article] [CI: 1] [IF: 5,8]
DOI: 10.1098/rsob.220062 SCOPUS: 85131218980
Soares D.S., Homem C.C.F., Castro D.S.,
Function of Proneural Genes Ascl1 and Asense in Neurogenesis: How Similar Are They?. Frontiers in Cell and Developmental Biology10:, 2022. [Journal: Review] [CI: 4] [IF: 5,5]
DOI: 10.3389/fcell.2022.838431 SCOPUS: 85125875412
Soares M.A.F., Soares D.S., Teixeira V., Heskol A., Bressan R.B., Pollard S.M., Oliveira R.A., Castro D.S.,
Hierarchical reactivation of transcription during mitosis-to-G1 transition by Brn2 and Ascl1 in neural stem cells. Genes and Development35(13):1020-1034, 2021. [Journal: Article] [CI: 10] [IF: 12,9]
DOI: 10.1101/GAD.348174.120 SCOPUS: 85110322843
Han S., Okawa S., Wilkinson G.A., Ghazale H., Adnani L., Dixit R., Tavares L., Faisal I., Brooks M.J., Cortay V., Zinyk D., Sivitilli A., Li S., Malik F., Ilnytskyy Y., Angarica V.E., Gao J., Chinchalongporn V., Oproescu A.M., Vasan L., Touahri Y., David L.A., Raharjo E., Kim J.W., Wu W., Rahmani W., Chan J.A.w., Kovalchuk I., Attisano L., Kurrasch D., Dehay C., Swaroop A., Castro D.S., Biernaskie J., del Sol A., Schuurmans C.,
Proneural genes define ground-state rules to regulate neurogenic patterning and cortical folding. Neuron109(18):2847-2863.e11, 2021. [Journal: Article] [CI: 16] [IF: 18,7]
DOI: 10.1016/j.neuron.2021.07.007 SCOPUS: 85115031365
Falcão A.M., Meijer M., Scaglione A., Rinwa P., Agirre E., Liang J., Larsen S.C., Heskol A., Frawley R., Klingener M., Varas-Godoy M., Raposo A.A.S.F., Ernfors P., Castro D.S., Nielsen M.L., Casaccia P., Castelo-Branco G.,
PAD2-Mediated Citrullination Contributes to Efficient Oligodendrocyte Differentiation and Myelination. Cell Reports27(4):1090-1102.e10, 2019. [Journal: Article] [CI: 46] [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: 39] [IF: 11,2]
DOI: 10.15252/embj.201797115 SCOPUS: 85050980313
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: 43] [IF: 8,3]
DOI: 10.1016/j.celrep.2016.09.024 SCOPUS: 85003935959
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: 48] [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: 127] [IF: 7,9]
DOI: 10.1016/j.celrep.2015.02.025 SCOPUS: 84931281902
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: 430] [IF: 33,1]
DOI: 10.1016/j.cell.2013.09.028 SCOPUS: 84886784309